3rd international symposium for medicinal...

– 1 –

3rd International Symposiumfor Medicinal Sciences

CONTENTS

1 Welcome Message 2

2 Notice for the Presenters and Attendants to the 3rd International Symposium for Medicinal Sciences 3

3 Programs at a Glance 6

4 Access and Venue Map 12

5 Program of 3rd International Symposium for Medicinal Sciences 18

6 Abstracts 24

Appendix

Abstracts Presented by English in 137th Annual Meeting of the Pharmaceutical Society of Japan

1. Programs 50

2. Abstracts 63

– 2 –

It is my great pleasure to hold the 3rd International Symposium for Medicinal Sciences in the 137th Annual Meeting

of Pharmaceutical Society of Japan. The objectives of this symposium are to encourage pharmaceutical company

researchers who are interested in drug discovery, to participate in this annual meeting, and also to create an important

international platform for all those interested in the medicinal sciences. Since this symposium covers the entire drug

discovery field, we welcome participants including pharmacology, pharmacokinetics, and regulatory sciences.

The one of the feature of this symposium is an invited poster presentations. Since high-caliber presentations from the

Japanese and foreign pharmaceutical industries, venture companies, and academia will line up in this presentation,

domestic young researchers who interested in the drug discovery, will have a good chance to discuss with the first

class researchers for drug discovery around the world.

Chairman of the 3rd International Symposium for Medicinal Sciences

Professor Akira OTAKA

(Institute of Biomedical Sciences and Graduate School of

Pharmaceutical Sciences, Tokushima University)

Notice to the Foreign Participants

This Abstract is contained all programs which will be presented by English in 137th Annual Meeting of the

Pharmaceutical Society of Japan other than 3rd International Symposium for Medicinal Sciences, as an appendix.

The appendix was involved the list of the programs and abstracts presented in English, including Special lectures,

Symposia, and general oral and poster presentations.

1 Welcome Message

– 3 –

1) RegistrationThe program & abstract book, conference ID/registration certificate will be handed at the registration desk, located

on the foyer, 2nd floor of Exhibition Building, Sendai International Center.

Registration Desk for Overseas participants will open during the meeting.

Registration Fee

Delegate: JPY 15,000

Student: JPY 5,000

Undergraduate student: * Free

* Undergraduate students will be required to present their student ID or student certificate letter at the

Registration Desk onsite.

Registration Fee includes

Admission to all scientific sessions

Admission to exhibition and posters

Meeting program & abstract book

Banquet

Date and Time: 18:30, Sunday, March 26

Venue: Room “Sendai” (4th floor), Hotel Metropolitan Sendai

Fee: JPY 15,000

Banquet tickets can be purchased at the registration desk.

2) General Information[Name badge]

Upon registration all participants will receive a name badge, which must be worn visibly for the entire duration

of the meeting. Your name badge acts as your entrance ticket for the meeting.

[Message board]

A message board will be placed near the registration desk. Participants can exchange messages through the

board.

[Camera, Mobile Phone and Video Recording Policies]

Attendees may not take photos or video of speakers presenting or their slides.

3) Area Map and VenueSee page 12-17

2 Notice for the Presenters and Attendants to the 3rd International Symposium for Medicinal Sciences

– 4 –

4) Guideline for Plenary Lectures– Plenary lecturers have 60 minutes (including Q&A).

– The session room only supports digital presentations using only one LCD projector.

– Please bring your power point file in a USB memory or PC to the speakers’ desk before your session, and

download/check your presentation data.

– The speakers’ desk will be placed in the foyer, 2nd floor of Conference Building.

– A Windows PC (with Windows 7, PowerPoint 2007, 2010, 2013, 2016) is available. If you are a Macintosh user

or wish to use moving images, please bring your own PC. Please make sure to bring an AC adapter, when you

bring your PC.

– Your PC will be connected to the projector with a “15-pin, mini D-sub” cable. Some PCs (Macintosh or thin

laptops) will require a conversion adapter.

– Please turn off the screen saver, power save mode.

– Set the resolution to XGA (1,024×768).

– After you finish your presentation, please receive your PC immediately inside the room.

– The organization committee will be responsible for deleting all copied data.

5) Guidelines for Poster Presentations

< Short Oral Presentation >

– You will be asked to make a short presentation (strictly 2 minutes).

Session Room: Room B “Tachibana Conference Hall”, 2nd floor of Conference Building

Presentation Time: 14:20-16:00

– Please bring your power point file in a USB memory to the speakers’ desk until 13:00 on the day of your

presentation, and make sure to check the presentation data. A Windows PC (with Windows 7, PowerPoint 2007,

2010, 2013, 2016) is only available.

– The speakers’ desk will be placed in the foyer, 2nd floor of Conference Building.

< Poster Presentation >

– Poster session room is located in Room G “Meeting Room 4” and the foyer, 2nd floor of Conference Building.

Abstracts scheduled for presentation in poster session will appear in the Symposium Program. Please refer to the

table below for setup, tear down, and presentation times for posters:

Set-Up8:30-9:00

11:45-13:15

Discussion Time16:00-17:40

Odd Number: 16:00-16:50Even Number: 16:50-17:40

Tear Down 17:40-18:00

– 5 –

– Each poster board is labeled with a number and check your poster number.

The poster board surface area is 2.1 m high by 1.2 m wide. Each poster should indicate the title of

presentation, name of authors and affiliations. Text should be printed in a font large enough to be read

comfortably from a distance of 4-5 feet (1.5m).

– Posters should be displayed on the boards using pushpins that will be available at the Poster Session room. No

other adhesive method is permitted on the boards.

"recommended usable area"“160×110cm”

– 6 –

Sendai International Center Sendai International Center Tohoku University

Centennial Hall

Tohoku University Kawauchi-Kita Campus

Conference Bldg Exhibition Bldg Exhibition Bldg Multimedia Education and Research Complex Lecture Rooms C

Room A Room B Room C Room D Room E Room F Room H Room I Room PA Room PB Room J Room K Room L Room M Room N Room O Room P Room Q Room R Room S Room T Room U Room V Room W Room X Room Y

2F 3F 1F 2F 1F 1F 2F 2F 2F 1F 2F 3FMain Hall Tachibana Hagi Shirakashi 1 Shirakashi 2 Meeting Room 8 Meeting Room 1 Meeting Room 2 Sakura Exhibition Hall Meeting Room 1 Meeting Room 2 Meeting Room 3 Kawauchi Hagi Hall Multimedia Research Hall Lecture room C101 C102 C105 C106 C201 C202 C205 C206 C301 C302

PosterPresentations

25PA-am001～

25PA-am140

【Discussion】Odd No.

9:45~10:45Even No.

10:45~11:45

PosterPresentations

25PB-am001～

25PB-am228


9:45~10:45Even No.

10:45~11:45

Plenary LecturePL

Naoto OKU

SymposiumS01

Let’s challenge practical

evidence-based medicine

educational program for pharmacy

students and pharmacists

SymposiumS02

New approaches of exploratory

study for preventive and

therapeutic targets in

neurodegenerative and psychiatric

disorders

OralPresentations

25F-am01～

25F-am13

OralPresentations

25H-am01～

25H-am13

OralPresentations

25I-am01～

25I-am13

SymposiumS03

How do we promote research integrity?

SymposiumS04

Risk assessment and management of a small amount of carcinogens

possibly exposed in our

ordinary life

SymposiumS05

Utilizing soft molecular

systems for drug discovery research ~the

concerted use of theory,

measurements and functional

design~

SymposiumS06

Research strategies

for the post-golden-age GPCR drug discovery

SymposiumS07

Role of pharmacy in the promotion of drug safety in

pharmacotherapy OralPresentations

25P-am01～

25P-am13

OralPresentations

25Q-am01～

25Q-am13

OralPresentations

25R-am01～

25R-am13

OralPresentations

25S-am01～

25S-am13

OralPresentations

25T-am01～

25T-am13

OralPresentations

25U-am01～

25U-am13

OralPresentations

25V-am01～

25V-am13

OralPresentations

25W-am01～

25W-am10

OralPresentations

25X-am01～

25X-am13

OralPresentations

25Y-am01～

25Y-am13

Award LecturesAL-1Takeo

KAWABATA

Award LecturesAL-10Toshihide

TAKEUCHI

Award LecturesAL-11

Hiroto HATAKEYAMA

Award LecturesAL-20

Naomi KURATA

Luncheon SeminarLS01

Japan EMF Information

Center

Luncheon SeminarLS02CRECON MEDICAL

ASSESSMENT INC.

Luncheon SeminarLS03Chugai

Pharmaceutical Co., LTD.

Luncheon SeminarLS04Agilent

Technologies Japan, Ltd.


Kyowa Chemical Industry Co., Ltd.


Ono Pharmaceutical

Co., Ltd. / AstraZeneca K. K.


SEED Co., Ltd.

Award LecturesAL-2

Kazuki SAITO

Award LecturesAL-12

Hiroki SHIGEHISA Symposium

S08

Effective communication

between pharmacists and foreign patients at

medical team

SymposiumS09

State-of-the-art technology

by young neuroscientists

SymposiumGS01

The front line and new progress in

cardiovascular research

-Searching for breakthrough

in treatments of cardiovascular

disease-Oral

Presentations

25F-pm01～

25F-pm17

OralPresentations

25H-pm01～

25H-pm17

OralPresentations

25I-pm01～

25I-pm17

PosterPresentations

25PA-pm001～

25PA-pm132


14:15~15:15Even No.

15:15~16:15

PosterPresentations

25PB-pm001～

25PB-pm307


14:15~15:15Even No.

15:15~16:15

SymposiumS10

Problem-Solving-Type Program for the Development

of Highly-Skilled Human

Resources(- Project for

Nurturing Pharmacists who

Provide Team-Based Community

Healthcare -)

SymposiumS11

Partnership for NTDs drug

discovery originated in

Japan

SymposiumS12

Structural biology of lipid-binding proteins

-Recent developments-

SymposiumS13

Young innovators

driving the next generation of

academic drug discovery

SymposiumS14

New Trends of Natural Products

Chemistry ― Redesign of Biosynthesis

OralPresentations

25P-pm01～

25P-pm16

OralPresentations

25Q-pm01～

25Q-pm17

OralPresentations

25R-pm01～

25R-pm17

OralPresentations

25S-pm01～

25S-pm16

OralPresentations

25T-pm01～

25T-pm16

OralPresentations

25U-pm01～

25U-pm17

OralPresentations

25V-pm01～

25V-pm17

OralPresentations

25W-pm01～

25W-pm15

OralPresentations

25X-pm01～

25X-pm17

OralPresentations

25Y-pm01～

25Y-pm17

Award LecturesAL-13Taniyuki

FURUYAMA

Special LecturesSL-1Hiro-o

HAMAGUCHI

Award LecturesAL-5Masaaki

KURIHARA

SymposiumS15

Challenges to improve

the prdiction accuacy of the

non-clinical tests for human CNS adverse effects:

Potentials of artificial

intelligence and human ESC/iPSC-derived

neurons

SymposiumS16

Fascination of sacran, a

polysaccharide from Aphanothece

sacrum

SymposiumGS02

The challenge of young

researchers leading the future and

development of the

pharmaceuticalresearch on

cancer

SymposiumS17

Current status of reverse

translational research

conducted by hospital

pharmacists

SymposiumS18

How can the researchers in university be involved with the stream of hospital

preparations from the

medical needs to the clinical application?

SymposiumS19

Scientific basis of plasma-

and mechano-biology in disease

therapy and drug delivery

towards clinicalapplications

SymposiumS20

Young Challengers in Synthetic

Organic Chemistry:

Deeper Understanding

and Recent Advancement

in Synthetic Organic

Chemistry

SymposiumS21

Modified nucleic acids

and regulation of diseases

Award LecturesAL-3

Hideo SAJI

Award LecturesAL-6

Hidetoshi ARAKAWA

Award LecturesAL-7Takashi SUZUKI

9:00

10:15

11:30

12:45

14:00

15:15

16:30

9:15

10:30

11:45

13:00

14:15

15:30

16:45

9:30

10:45

12:00

13:15

14:30

15:45

17:00

9:45

11:00

12:15

13:30

14:45

16:00

17:15

10:00

11:15

12:30

13:45

15:00

16:15

17:30

17:45

18:00

25 March (Sat)

16:39

11:36 11:36

16:39

11:36

16:39

8:45

14:40

16:35

17:40

16:50

24 March (Fri)Sendai International Center

Conference Bldg

Room A

2FMain Hall

General Assembly

9:00

10:15

11:30

12:45

14:00

15:15

16:30

9:15

10:30

11:45

13:00

14:15

15:30

16:45

9:30

10:45

12:00

13:15

14:30

15:45

17:00

9:45

11:00

12:15

13:30

14:45

16:00

17:15

10:00

11:15

12:30

13:45

15:00

16:15

17:30

17:45

18:00

8:45

3 Programs at a Glance

E : English Presentation

– 7 –

Sendai International Center Sendai International Center Tohoku University

Centennial Hall


Conference Bldg Exhibition Bldg Exhibition Bldg Multimedia Education and Research Complex Lecture Rooms C


2F 3F 1F 2F 1F 1F 2F 2F 2F 1F 2F 3FMain Hall Tachibana Hagi Shirakashi 1 Shirakashi 2 Meeting Room 8 Meeting Room 1 Meeting Room 2 Sakura Exhibition Hall Meeting Room 1 Meeting Room 2 Meeting Room 3 Kawauchi Hagi Hall Multimedia Research Hall Lecture room C101 C102 C105 C106 C201 C202 C205 C206 C301 C302

PosterPresentations

25PA-am001～

25PA-am140


9:45~10:45Even No.

10:45~11:45

PosterPresentations

25PB-am001～

25PB-am228


9:45~10:45Even No.

10:45~11:45

Plenary LecturePL

Naoto OKU

SymposiumS01

Let’s challenge practical

evidence-based medicine

educational program for pharmacy

students and pharmacists

SymposiumS02

New approaches of exploratory

study for preventive and

therapeutic targets in

neurodegenerative and psychiatric

disorders

OralPresentations

25F-am01～

25F-am13

OralPresentations

25H-am01～

25H-am13

OralPresentations

25I-am01～

25I-am13

SymposiumS03

How do we promote research integrity?

SymposiumS04

Risk assessment and management of a small amount of carcinogens

possibly exposed in our

ordinary life

SymposiumS05

Utilizing soft molecular

systems for drug discovery research ~the

concerted use of theory,

measurements and functional

design~

SymposiumS06

Research strategies

for the post-golden-age GPCR drug discovery

SymposiumS07

Role of pharmacy in the promotion of drug safety in

pharmacotherapy OralPresentations

25P-am01～

25P-am13

OralPresentations

25Q-am01～

25Q-am13

OralPresentations

25R-am01～

25R-am13

OralPresentations

25S-am01～

25S-am13

OralPresentations

25T-am01～

25T-am13

OralPresentations

25U-am01～

25U-am13

OralPresentations

25V-am01～

25V-am13

OralPresentations

25W-am01～

25W-am10

OralPresentations

25X-am01～

25X-am13

OralPresentations

25Y-am01～

25Y-am13

Award LecturesAL-1Takeo

KAWABATA

Award LecturesAL-10Toshihide

TAKEUCHI

Award LecturesAL-11

Hiroto HATAKEYAMA

Award LecturesAL-20

Naomi KURATA


Japan EMF Information

Center

Luncheon SeminarLS02CRECON MEDICAL

ASSESSMENT INC.

Luncheon SeminarLS03Chugai

Pharmaceutical Co., LTD.

Luncheon SeminarLS04Agilent

Technologies Japan, Ltd.


Kyowa Chemical Industry Co., Ltd.


Ono Pharmaceutical

Co., Ltd. / AstraZeneca K. K.


SEED Co., Ltd.

Award LecturesAL-2

Kazuki SAITO

Award LecturesAL-12

Hiroki SHIGEHISA Symposium

S08

Effective communication

between pharmacists and foreign patients at

medical team

SymposiumS09

State-of-the-art technology

by young neuroscientists

SymposiumGS01

The front line and new progress in

cardiovascular research

-Searching for breakthrough

in treatments of cardiovascular

disease-Oral

Presentations

25F-pm01～

25F-pm17

OralPresentations

25H-pm01～

25H-pm17

OralPresentations

25I-pm01～

25I-pm17

PosterPresentations

25PA-pm001～

25PA-pm132


14:15~15:15Even No.

15:15~16:15

PosterPresentations

25PB-pm001～

25PB-pm307


14:15~15:15Even No.

15:15~16:15

SymposiumS10

Problem-Solving-Type Program for the Development

of Highly-Skilled Human

Resources(- Project for

Nurturing Pharmacists who

Provide Team-Based Community

Healthcare -)

SymposiumS11

Partnership for NTDs drug

discovery originated in

Japan

SymposiumS12

Structural biology of lipid-binding proteins

-Recent developments-

SymposiumS13

Young innovators

driving the next generation of

academic drug discovery

SymposiumS14

New Trends of Natural Products

Chemistry ― Redesign of Biosynthesis

OralPresentations

25P-pm01～

25P-pm16

OralPresentations

25Q-pm01～

25Q-pm17

OralPresentations

25R-pm01～

25R-pm17

OralPresentations

25S-pm01～

25S-pm16

OralPresentations

25T-pm01～

25T-pm16

OralPresentations

25U-pm01～

25U-pm17

OralPresentations

25V-pm01～

25V-pm17

OralPresentations

25W-pm01～

25W-pm15

OralPresentations

25X-pm01～

25X-pm17

OralPresentations

25Y-pm01～

25Y-pm17

Award LecturesAL-13Taniyuki

FURUYAMA

Special LecturesSL-1Hiro-o

HAMAGUCHI

Award LecturesAL-5Masaaki

KURIHARA

SymposiumS15

Challenges to improve

the prdiction accuacy of the

non-clinical tests for human CNS adverse effects:

Potentials of artificial

intelligence and human ESC/iPSC-derived

neurons

SymposiumS16

Fascination of sacran, a

polysaccharide from Aphanothece

sacrum

SymposiumGS02

The challenge of young

researchers leading the future and

development of the

pharmaceuticalresearch on

cancer

SymposiumS17

Current status of reverse

translational research

conducted by hospital

pharmacists

SymposiumS18

How can the researchers in university be involved with the stream of hospital

preparations from the

medical needs to the clinical application?

SymposiumS19

Scientific basis of plasma-

and mechano-biology in disease

therapy and drug delivery

towards clinicalapplications

SymposiumS20

Young Challengers in Synthetic

Organic Chemistry:

Deeper Understanding

and Recent Advancement

in Synthetic Organic

Chemistry

SymposiumS21

Modified nucleic acids

and regulation of diseases

Award LecturesAL-3

Hideo SAJI

Award LecturesAL-6

Hidetoshi ARAKAWA

Award LecturesAL-7Takashi SUZUKI

11:36 11:36 11:36 11:36 11:3611:36 11:36 11:36 11:36

16:27

16:39 16:39

16:27 16:27

16:39 16:39

16:03

16:39 16:39

9:00

10:15

11:30

12:45

14:00

15:15

16:30

9:15

10:30

11:45

13:00

14:15

15:30

16:45

9:30

10:45

12:00

13:15

14:30

15:45

17:00

9:45

11:00

12:15

13:30

14:45

16:00

17:15

10:00

11:15

12:30

13:45

15:00

16:15

17:30

17:45

18:00

8:45

– 8 –

Sendai International Center Tohoku University

Centennial Hall

Tohoku University Kawauchi-Kita Campus Sendai Civic AuditoriumConference Bldg Exhibition Bldg Multimedia Education and

Research Complex Lecture Rooms C

Room A Room B Room C Room D Room E Room F Room H Room I Room G Room PA Room PB Room J Room K Room L Room M Room N Room O Room P Room Q Room R Room S Room T Room U Room V Room W Room X Room Y Room Z

2F 3F 1F 2F 1F 2F 2F 2F 1F 2F 3FMain Hall Tachibana Hagi Shirakashi 1 Shirakashi 2 Meeting Room 8 Meeting Room 1 Meeting Room 2 Meeting Room 4 Sakura Exhibition Hall Meeting Room 1 Meeting Room 2 Meeting Room 3 Kawauchi Hagi Hall Multimedia Research Hall Lecture room C101 C102 C105 C106 C201 C202 C205 C206 C301 C302

PosterPresentations

26PA-am001～

26PA-am140


9:45~10:45Even No.

10:45~11:45

PosterPresentations

26PB-am001～

26PB-am335


9:45~10:45Even No.

10:45~11:45

Special LecturesSL-2

Eric KOOL

Award LecturesAL-18Tomokazu

YOSHINAGA

Award LecturesAL-14

Toru KOMATSU Symposium

S22

Recent advances in clinical

chemistry for developing novel drug treatment strategies

SymposiumGS03

Frontier of translational

research by young

investigators aim to innovative drug discovery

and drug fostering

OralPresentations

26F-am01～

26F-am13

OralPresentations

26H-am01～

26H-am13

OralPresentations

26I-am01～

26I-am13

SymposiumOS23

Creation of Complex

Functional Molecules by Rational Redesign of Biosynthetic Machineries

SymposiumS24

Appropriate planning and management

of annual meeting for

all attendees; application of active learning

SymposiumS25

The structural studies of membrane proteins by

leading edge technologies:

their forthcoming contribution to pharmacology

and drug development


Alexander MAKAROV

SymposiumS26

Currents state and future

prospects of doctoral course

for students graduated

from division of pharmacy (4-year program)

- A survey commissioned to PSJ from the

MEXT

SymposiumS27

The efforts by pharmacists to

implement home medical care for heart failure - a comprehensive

integrated community care -

OralPresentations

26P-am01～

26P-am13

OralPresentations

26Q-am01～

26Q-am13

OralPresentations

26R-am01～

26R-am13

OralPresentations

26S-am01～

26S-am13

OralPresentations

26T-am01～

26T-am13

OralPresentations

26U-am01～

26U-am13

OralPresentations

26V-am01～

26V-am13

OralPresentations

26W-am01～

26W-am12

OralPresentations

26X-am01～

26X-am12

OralPresentations

26Y-am01～

26Y-am13

Award LecturesAL-15

Kazuya NAGANOAward Lectures

AL-19Nobuhiro OIKAWA


Takuzo AIDA

Special LecturesSL-8Hidenori ICHIJO

Award LecturesAL-16

Hideyuki KONISHI

International Symposium for Medicinal

SciencesISMS-PL01

Ross D. KING

Award LecturesAL-17

Jun SHIMOKAWA

Award LecturesAL-4Shigeki SASAKI

Luncheon SeminarLS08SCIEX


Shimadzu Corporation

Luncheon SeminarLS10Astellas

Pharma Inc.


Thermo Fisher Scientific

Luncheon SeminarLS12Sawai

Pharmaceutical Co., Ltd.


Daiichi Sankyo Company / Mitsubishi

Tanabe Pharma Corporation

Luncheon SeminarLS14Otsuka



Masayuki YAMAMOTO


SciencesISMS-PL02

SriramSUBRAMANIAM

SymposiumOS28

PSJ's organizational

approach to the promotion of

gender equality

SymposiumGS04

Approach to the Next Remedy by

Multidiscipline Researchers

-for Responding to Unmet

Medical Needs-Oral

Presentations

26F-pm01～

26F-pm17

OralPresentations

26H-pm01～

26H-pm17

OralPresentations

26I-pm01～

26I-pm17

PosterPresentations

26PA-pm001～

26PA-pm133


14:15~15:15Even No.

15:15~16:15

PosterPresentations

26PB-pm001～

26PB-pm312


14:15~15:15Even No.

15:15~16:15

SymposiumS29

New development of the risk benefit communication

- For safety information to be communicatedand understood

sufficiently-

SymposiumS30

The mechanisms of epileptogenesis and the effective

intervention strategies in pediatric and elderly patients

SymposiumS31

Cutting edge of retinal circuit

research

Special LecturesSL-9Katsumi

MATSUZAKI

SymposiumS32

Forefront of cancer targeting therapy

OralPresentations

26P-pm01～

26P-pm17

OralPresentations

26Q-pm01～

26Q-pm17

OralPresentations

26R-pm01～

26R-pm16

OralPresentations

26S-pm01～

26S-pm13

OralPresentations

26T-pm01～

26T-pm17

OralPresentations

26U-pm01～

26U-pm17

OralPresentations

26V-pm01～

26V-pm17

OralPresentations

26W-pm01～

26W-pm17

OralPresentations

26X-pm01～

26X-pm17

OralPresentations

26Y-pm01～

26Y-pm11

Public Lecture


SciencesISMS:

Poster Short Presentation


Ruedi AEBERSOLD


Keiji MARUOKA

SymposiumOS33

FIP forum 2017: International educational trends for

pharmaceutical researchers in the next generation

Award LecturesAL-8Yaichiro KOTAKE

SymposiumS34

Protectioun of Skin from Dryness and UV Radiation

-Approach from Cosmetics-

SymposiumS35

Progress of health care information

technologies- On-site

inflection of the new information technologies -

SymposiumS36

For promotion of the

participation of the pharmacist

to home medical care

SymposiumS37

Frontiers in immunology for innovative drug development

SymposiumS38

Frontiers of Research

on Anti-Viral Infectious Diseases-Boundary

between Host Defense and Viral Offense-


Christina WHITE


SciencesISMS:Poster

Presentation


SciencesISMS:Poster

PresentationAward Lectures

AL-9Mitsuhiro ARISAWA

26 March (Sun)

16:39

11:36 11:36

16:27

11:36

16:39

9:00

10:15

11:30

12:45

14:00

15:15

16:30

9:15

10:30

11:45

13:00

14:15

15:30

16:45

9:30

10:45

12:00

13:15

14:30

15:45

17:00

9:45

11:00

12:15

13:30

14:45

16:00

17:15

10:00

11:15

12:30

13:45

15:00

16:15

17:30

17:45

18:00

8:45

9:40

10:25

10:40

16:10

9:40

10:10

10:20

10:50

16:50

14:20

17:4017:40

E


E

E

E

E

E

E

E

E

– 9 –


Centennial Hall

Tohoku University Kawauchi-Kita Campus Sendai Civic AuditoriumConference Bldg Exhibition Bldg Multimedia Education and

Research Complex Lecture Rooms C

Room A Room B Room C Room D Room E Room F Room H Room I Room G Room PA Room PB Room J Room K Room L Room M Room N Room O Room P Room Q Room R Room S Room T Room U Room V Room W Room X Room Y Room Z

2F 3F 1F 2F 1F 2F 2F 2F 1F 2F 3FMain Hall Tachibana Hagi Shirakashi 1 Shirakashi 2 Meeting Room 8 Meeting Room 1 Meeting Room 2 Meeting Room 4 Sakura Exhibition Hall Meeting Room 1 Meeting Room 2 Meeting Room 3 Kawauchi Hagi Hall Multimedia Research Hall Lecture room C101 C102 C105 C106 C201 C202 C205 C206 C301 C302

PosterPresentations

26PA-am001～

26PA-am140


9:45~10:45Even No.

10:45~11:45

PosterPresentations

26PB-am001～

26PB-am335


9:45~10:45Even No.

10:45~11:45


Eric KOOL

Award LecturesAL-18Tomokazu

YOSHINAGA

Award LecturesAL-14

Toru KOMATSU Symposium

S22

Recent advances in clinical

chemistry for developing novel drug treatment strategies

SymposiumGS03

Frontier of translational

research by young

investigators aim to innovative drug discovery

and drug fostering

OralPresentations

26F-am01～

26F-am13

OralPresentations

26H-am01～

26H-am13

OralPresentations

26I-am01～

26I-am13

SymposiumOS23

Creation of Complex

Functional Molecules by Rational Redesign of Biosynthetic Machineries

SymposiumS24

Appropriate planning and management

of annual meeting for

all attendees; application of active learning

SymposiumS25

The structural studies of membrane proteins by

leading edge technologies:

their forthcoming contribution to pharmacology

and drug development


Alexander MAKAROV

SymposiumS26

Currents state and future

prospects of doctoral course

for students graduated

from division of pharmacy (4-year program)

- A survey commissioned to PSJ from the

MEXT

SymposiumS27

The efforts by pharmacists to

implement home medical care for heart failure - a comprehensive

integrated community care -

OralPresentations

26P-am01～

26P-am13

OralPresentations

26Q-am01～

26Q-am13

OralPresentations

26R-am01～

26R-am13

OralPresentations

26S-am01～

26S-am13

OralPresentations

26T-am01～

26T-am13

OralPresentations

26U-am01～

26U-am13

OralPresentations

26V-am01～

26V-am13

OralPresentations

26W-am01～

26W-am12

OralPresentations

26X-am01～

26X-am12

OralPresentations

26Y-am01～

26Y-am13

Award LecturesAL-15

Kazuya NAGANOAward Lectures

AL-19Nobuhiro OIKAWA


Takuzo AIDA

Special LecturesSL-8Hidenori ICHIJO

Award LecturesAL-16

Hideyuki KONISHI


SciencesISMS-PL01

Ross D. KING

Award LecturesAL-17

Jun SHIMOKAWA

Award LecturesAL-4Shigeki SASAKI

Luncheon SeminarLS08SCIEX


Shimadzu Corporation

Luncheon SeminarLS10Astellas

Pharma Inc.


Thermo Fisher Scientific

Luncheon SeminarLS12Sawai



Daiichi Sankyo Company / Mitsubishi

Tanabe Pharma Corporation

Luncheon SeminarLS14Otsuka



Masayuki YAMAMOTO


SciencesISMS-PL02

SriramSUBRAMANIAM

SymposiumOS28

PSJ's organizational

approach to the promotion of

gender equality

SymposiumGS04

Approach to the Next Remedy by

Multidiscipline Researchers

-for Responding to Unmet

Medical Needs-Oral

Presentations

26F-pm01～

26F-pm17

OralPresentations

26H-pm01～

26H-pm17

OralPresentations

26I-pm01～

26I-pm17

PosterPresentations

26PA-pm001～

26PA-pm133


14:15~15:15Even No.

15:15~16:15

PosterPresentations

26PB-pm001～

26PB-pm312


14:15~15:15Even No.

15:15~16:15

SymposiumS29

New development of the risk benefit communication

- For safety information to be communicatedand understood

sufficiently-

SymposiumS30

The mechanisms of epileptogenesis and the effective

intervention strategies in pediatric and elderly patients

SymposiumS31

Cutting edge of retinal circuit

research

Special LecturesSL-9Katsumi

MATSUZAKI

SymposiumS32

Forefront of cancer targeting therapy

OralPresentations

26P-pm01～

26P-pm17

OralPresentations

26Q-pm01～

26Q-pm17

OralPresentations

26R-pm01～

26R-pm16

OralPresentations

26S-pm01～

26S-pm13

OralPresentations

26T-pm01～

26T-pm17

OralPresentations

26U-pm01～

26U-pm17

OralPresentations

26V-pm01～

26V-pm17

OralPresentations

26W-pm01～

26W-pm17

OralPresentations

26X-pm01～

26X-pm17

OralPresentations

26Y-pm01～

26Y-pm11

Public Lecture


SciencesISMS:

Poster Short Presentation


Ruedi AEBERSOLD


Keiji MARUOKA

SymposiumOS33

FIP forum 2017: International educational trends for

pharmaceutical researchers in the next generation

Award LecturesAL-8Yaichiro KOTAKE

SymposiumS34

Protectioun of Skin from Dryness and UV Radiation

-Approach from Cosmetics-

SymposiumS35

Progress of health care information

technologies- On-site

inflection of the new information technologies -

SymposiumS36

For promotion of the

participation of the pharmacist

to home medical care

SymposiumS37

Frontiers in immunology for innovative drug development

SymposiumS38

Frontiers of Research

on Anti-Viral Infectious Diseases-Boundary

between Host Defense and Viral Offense-


Christina WHITE


SciencesISMS:Poster

Presentation


SciencesISMS:Poster

PresentationAward Lectures

AL-9Mitsuhiro ARISAWA

11:36

16:39

11:36

16:27

11:36

15:51

11:36

16:39

11:36

16:39

11:36

16:3916:39

11:36

11:24

16:39

11:12

16:39

15:27

9:00

10:15

11:30

12:45

14:00

15:15

16:30

9:15

10:30

11:45

13:00

14:15

15:30

16:45

9:30

10:45

12:00

13:15

14:30

15:45

17:00

9:45

11:00

12:15

13:30

14:45

16:00

17:15

10:00

11:15

12:30

13:45

15:00

16:15

17:30

17:45

18:00

8:45

11:36

Hotel Metropolitan Sendai

Banquet (buffet style)18:30

E

– 10 –


Centennial Hall


Conference Bldg Exhibition Bldg Multimedia Education and Research Complex Lecture Rooms C


2F 3F 1F 2F 1F 2F 2F 2F 1F 2F 3FMain Hall Tachibana Hagi Shirakashi 1 Shirakashi 2 Meeting Room 8 Meeting Room 1 Meeting Room 2 Sakura Exhibition Hall Meeting Room 1 Meeting Room 2 Meeting Room 3 Kawauchi Hagi Hall Multimedia Research Hall Lecture room C101 C102 C105 C106 C201 C202 C205 C206 C301 C302

PosterPresentations

27PA-am001～

27PA-am141


9:45~10:45Even No.

10:45~11:45

PosterPresentations

27PB-am001～

27PB-am255


9:45~10:45Even No.

10:45~11:45

SymposiumS39

Recent advances in DDS research on the key molecule "cell-

penetrating peptides" that controls the

kinetics of the next-generation drug target "biopharmaceuticals"

SymposiumS40

Catalysis Bridging Material

Science and Life Science

SymposiumS41

Lifestyle inspires future

pharmacotherapy and drug discovery

OralPresentations

27E-am01～

27E-am09

OralPresentations

27F-am01～

27F-am13

OralPresentations

27H-am01～

27H-am13

OralPresentations

27I-am01～

27I-am13

SymposiumOS42

PSJ-PSK Joint Symposium:

The mechanism, evaluation,

prediction and diagnosis of drug-induced

liver injury

SymposiumS43

Recent advances in

the networking and crosstalk

through several organs

to affect the homeostasis of living organism

SymposiumS44

Various physiological

actions mediated

through a Na+/ glucose co-transporter

(SGLT) and the possibility of the innovative drug development

SymposiumS45

Novel Development of Toxicology

Studies of Chemicals

SymposiumS46

Pharmaceutical Compounds in

the Environment -Distribution,

Ecological effects, and PurificationTechnologies-

OralPresentations

27P-am01～

27P-am13

OralPresentations

27Q-am01～

27Q-am12

OralPresentations

27R-am01～

27R-am12

OralPresentations

27S-am01～

27S-am12

OralPresentations

27T-am01～

27T-am13

OralPresentations

27U-am01～

27U-am13

OralPresentations

27V-am01～

27V-am13

OralPresentations

27W-am01～

27W-am13

OralPresentations

27X-am01～

27X-am13

SymposiumS50

Knowledge of drug

interactions to take

advantage in the pharmacist


Live Cell Super-Resolution Imaging

Research Team RIKEN Center for Advanced

Photonics

Nobel Lecture Broadcasting

(Live)

SymposiumS47

Symposium of The Division of Physical

Sciences of the Pharmaceutical

Society of Japan

SymposiumS48

Frontier of the middle size

drug discovery-Middle

molecular strategy: Creation of higher

biofunctional molecules

by integrated synthesis-

SymposiumS49

Metallomic research based on determining the relationship

between biometals and biological

reactions: From investigation of the important

role of biometals to establishment

of novel pharmacotherapy for major diseases

OralPresentations

27E-pm01～

27E-pm14

OralPresentations

27F-pm01～

27F-pm17

OralPresentations

27H-pm02～

27H-pm17

OralPresentations

27I-pm01～

27I-pm17

PosterPresentations

27PA-pm001～

27PA-pm136


14:15~15:15Even No.

15:15~16:15

PosterPresentations

27PB-pm001～

27PB-pm191


14:15~15:15Even No.

15:15~16:15

SymposiumS51

Evaluation and guarantee

of quality of pharmaceutical education by

the Japan Accreditation

Board for Pharmaceutical

Education

SymposiumS52

Platform development

for drug discovery utilizing silkworm

towards "Novel Industrial

Revolution"

Nobel Lecture

NLYoshinori OHSUMI

SymposiumS53

Frontier Pharmaceutics to Be Explored by

Young Scientists: Opening Up

New Horizon of Pharmaceutics for Next Generation Innovative Drug Discovery and

Development using Nanoscience and Nanotechnology

SymposiumS54

Frontier of biomedical science by

biomolecule analysis based

on mass spectrometry

OralPresentations

27P-pm01～

27P-pm09

OralPresentations

27Q-pm01～

27Q-pm12

OralPresentations

27R-pm01～

27R-pm16

OralPresentations

27S-pm01～

27S-pm17

OralPresentations

27T-pm01～

27T-pm17

OralPresentations

27U-pm01～

27U-pm04

OralPresentations

27V-pm01～

27V-pm17

OralPresentations

27W-pm01～

27W-pm14

OralPresentations

27X-pm01～

27X-pm06


(recorded)

SymposiumS55

Chemical Biology for

Pharmaceutical Sciences

(Development of practical chemical

biotechnology)

SymposiumS56

Frontier of Synthetic Organic

Chemistry Opened by Precisely Designed

Catalysts with Specified Field

SymposiumS57

Iron Ion as a New Target for Drug Discovery

SymposiumS58

Current trends in analytical technologies

which promote the development of

biopharmaceuticals

SymposiumS59

An explosion of photoswichable molecules for

spatiotemporal visualization

and control of biological activity


(recorded)

27 March (Mon)

11:36

10:48

16:39

11:36

16:15

11:36

16:39

16:03

9:00

10:15

11:30

12:45

14:00

15:15

16:30

9:15

10:30

11:45

13:00

14:15

15:30

16:45

9:30

10:45

12:00

13:15

14:30

15:45

17:00

9:45

11:00

12:15

13:30

14:45

16:00

17:15

10:00

11:15

12:30

13:45

15:00

16:15

17:30

17:45

18:00

8:45


E

– 11 –


Centennial Hall


Conference Bldg Exhibition Bldg Multimedia Education and Research Complex Lecture Rooms C


2F 3F 1F 2F 1F 2F 2F 2F 1F 2F 3FMain Hall Tachibana Hagi Shirakashi 1 Shirakashi 2 Meeting Room 8 Meeting Room 1 Meeting Room 2 Sakura Exhibition Hall Meeting Room 1 Meeting Room 2 Meeting Room 3 Kawauchi Hagi Hall Multimedia Research Hall Lecture room C101 C102 C105 C106 C201 C202 C205 C206 C301 C302

PosterPresentations

27PA-am001～

27PA-am141


9:45~10:45Even No.

10:45~11:45

PosterPresentations

27PB-am001～

27PB-am255


9:45~10:45Even No.

10:45~11:45

SymposiumS39

Recent advances in DDS research on the key molecule "cell-

penetrating peptides" that controls the

kinetics of the next-generation drug target "biopharmaceuticals"

SymposiumS40

Catalysis Bridging Material

Science and Life Science

SymposiumS41

Lifestyle inspires future

pharmacotherapy and drug discovery

OralPresentations

27E-am01～

27E-am09

OralPresentations

27F-am01～

27F-am13

OralPresentations

27H-am01～

27H-am13

OralPresentations

27I-am01～

27I-am13

SymposiumOS42

PSJ-PSK Joint Symposium:

The mechanism, evaluation,

prediction and diagnosis of drug-induced

liver injury

SymposiumS43

Recent advances in

the networking and crosstalk

through several organs

to affect the homeostasis of living organism

SymposiumS44

Various physiological

actions mediated

through a Na+/ glucose co-transporter

(SGLT) and the possibility of the innovative drug development

SymposiumS45

Novel Development of Toxicology

Studies of Chemicals

SymposiumS46

Pharmaceutical Compounds in

the Environment -Distribution,

Ecological effects, and PurificationTechnologies-

OralPresentations

27P-am01～

27P-am13

OralPresentations

27Q-am01～

27Q-am12

OralPresentations

27R-am01～

27R-am12

OralPresentations

27S-am01～

27S-am12

OralPresentations

27T-am01～

27T-am13

OralPresentations

27U-am01～

27U-am13

OralPresentations

27V-am01～

27V-am13

OralPresentations

27W-am01～

27W-am13

OralPresentations

27X-am01～

27X-am13

SymposiumS50

Knowledge of drug

interactions to take

advantage in the pharmacist


Live Cell Super-Resolution Imaging

Research Team RIKEN Center for Advanced

Photonics


(Live)

SymposiumS47

Symposium of The Division of Physical

Sciences of the Pharmaceutical

Society of Japan

SymposiumS48

Frontier of the middle size

drug discovery-Middle

molecular strategy: Creation of higher

biofunctional molecules

by integrated synthesis-

SymposiumS49

Metallomic research based on determining the relationship

between biometals and biological

reactions: From investigation of the important

role of biometals to establishment

of novel pharmacotherapy for major diseases

OralPresentations

27E-pm01～

27E-pm14

OralPresentations

27F-pm01～

27F-pm17

OralPresentations

27H-pm02～

27H-pm17

OralPresentations

27I-pm01～

27I-pm17

PosterPresentations

27PA-pm001～

27PA-pm136


14:15~15:15Even No.

15:15~16:15

PosterPresentations

27PB-pm001～

27PB-pm191


14:15~15:15Even No.

15:15~16:15

SymposiumS51

Evaluation and guarantee

of quality of pharmaceutical education by

the Japan Accreditation

Board for Pharmaceutical

Education

SymposiumS52

Platform development

for drug discovery utilizing silkworm

towards "Novel Industrial

Revolution"

Nobel Lecture

NLYoshinori OHSUMI

SymposiumS53

Frontier Pharmaceutics to Be Explored by

Young Scientists: Opening Up

New Horizon of Pharmaceutics for Next Generation Innovative Drug Discovery and

Development using Nanoscience and Nanotechnology

SymposiumS54

Frontier of biomedical science by

biomolecule analysis based

on mass spectrometry

OralPresentations

27P-pm01～

27P-pm09

OralPresentations

27Q-pm01～

27Q-pm12

OralPresentations

27R-pm01～

27R-pm16

OralPresentations

27S-pm01～

27S-pm17

OralPresentations

27T-pm01～

27T-pm17

OralPresentations

27U-pm01～

27U-pm04

OralPresentations

27V-pm01～

27V-pm17

OralPresentations

27W-pm01～

27W-pm14

OralPresentations

27X-pm01～

27X-pm06


(recorded)

SymposiumS55

Chemical Biology for

Pharmaceutical Sciences

(Development of practical chemical

biotechnology)

SymposiumS56

Frontier of Synthetic Organic

Chemistry Opened by Precisely Designed

Catalysts with Specified Field

SymposiumS57

Iron Ion as a New Target for Drug Discovery

SymposiumS58

Current trends in analytical technologies

which promote the development of

biopharmaceuticals

SymposiumS59

An explosion of photoswichable molecules for

spatiotemporal visualization

and control of biological activity


(recorded)

14:03

15:39

16:27

16:39 16:39

15:03

16:39

16:03

14:27

11:24 11:24 11:24

11:36 11:3611:36 11:36 11:36 11:36

9:00

10:15

11:30

12:45

14:00

15:15

16:30

9:15

10:30

11:45

13:00

14:15

15:30

16:45

9:30

10:45

12:00

13:15

14:30

15:45

17:00

9:45

11:00

12:15

13:30

14:45

16:00

17:15

10:00

11:15

12:30

13:45

15:00

16:15

17:30

17:45

18:00

8:45

– 12 –

◆Access

◆Map

Sendai Airport

on foot 3min.

on foot 15min.

on foot 10min.on foot 7min.

Subway Tozai - Line: 6min. [200 yen]

Subway Tozai - Line: 5min. [200 yen]

TAXI: 12min. [1,200 yen]

TAXI: 10min. [1,000 yen]

on foot 10min.on foot 3min. on foot 10min.

Sendai Airport Access Line: 17min. - 25min. [650 yen]

ＪＲ Sendai Station（West Entrance）

Sendai International CenterTohoku Univ.

Kawauchi-Kita CampusTohoku Univ. Centennial Hall: Kawauchi Hagi Hall

Subway Tozai - Line: Kawauchi Station

Subway Tozai - Line: International Center Station

By Air

By Train

Sendai International CenterHotel Metropolitan Sendai

(Banquet on March 26)Tohoku Univ. Centennial Hall: Kawauchi Hagi Hall

Tohoku Univ.Kawauchi-Kita Campus

Access4 Access and Venue Map

– 13 –

Area Map

0 100m50

P Ougi-zaka(80-step)

Subway Kawauchi Station

Subway International Center Station

Subway International Center Station

Tohoku Univ.Main Library

Aoba Castle Facility

Convenience Store

Sendai City Museum(Under Construction)

The Miyagi Museum of Art

Tohoku Univ.Multimedia Research Hall

Tohoku Univ.Lecture Rooms C

Sendai International Center Conference Bldg.

Sendai International Center Exhibition Bldg.

Tohoku Univ. Centennial Hall: Kawauchi Hagi Hall

Room PlaceA, B, C, D, E, F, G, H, I, PA Sendai International Center Conference Bldg.J, K, L, PB Sendai International Center Exhibition Bldg.M Kawauchi Hagi HallN Kawauchi-Kita Campus: Multimedia Research HallO, P, Q, R, S, T, U, V, W, X, Y Kawauchi-Kita Campus: Kawauchi Lecture Rooms C

Exhibition PlaceExhibition Room Sendai International Center Exhibition Bldg. Exhibition Hall 2

Registration Place

Registration & Information DeskSendai International Center Exhibition Bldg. FoyerKawauchi-Kita Campus: Kawauchi Lecture Rooms C １F C103

PC CenterSendai International Center Conference Bldg. 2F LobbyKawauchi-Kita Campus: Kawauchi Lecture Rooms C ２F C203

Banquet Hotel Metropolitan Sendai 4F 「千代（Sendai）」

– 14 –

2F Lobby

EV

EV

EV

Conference Bldg. 1F

Conference Bldg. 2F

Sendai International Center

Room: H【Meeting Room 1】

Room: I【Meeting Room 2】

Cloak②

EntranceReception【Cafe "Leaf"】

Room: PA【Sakura】

Room: A【Main Hall】

Room: B【Tachibana】

Room: C【Hagi】

Secretariat【Meeting Room 5】

Room: G【Meeting Room 4】to Exhibition Bldg.

PC Center

– 15 –

Foyer

EV

Exhibition Seminar【Meeting Room 4】

Conference Bldg. 3F

Exhibition Bldg.

Room: F【Meeting Room 8】

Room: E【Shirakashi 2】

Room: D【Shirakashi 1】

Room: K【Meeting Room 2】

Room: L【Meeting Room 3】

Room: J【Meeting Room 1】 Room: PB

【Exhibition Hall 1】Exhibition Room【Exhibition Hall 2】

to Conference Bldg. 2Fto Conference Bldg. 1F

from Subway International Center Station

Cloak①

Poster Room Information

Registration & Information Desk Lunchtime Seminars Ticket Counter

– 16 –

バーコーナーEV

Foyer

EV

1F

2F

Tohoku University Centennial Hall Kawauchi Hagi Hall

PC Center【1F Lobby】

Room: M【Hagi Hall】

Entrance

PC Center

– 17 –

EV

EV

Multimedia Education and Research Complex 2F

Lecture Rooms C 1F


Multimedia Education and Research Complex 1F

Lecture Rooms C 2F

Lecture Rooms C 3F

Room: O【Lecture room】

Room: N【Multimedia Research Hall】

【M206】

Room: P【C101】

Room: Q【C102】

Room: R【C105】

Cloak③【C104】

【C103】

PC Center【C203】

Room: S【C106】

Room: T【C201】

Room: U【C202】

Room: V【C205】

Room: W【C206】

Room: X【C301】

Room: Y【C302】

PC Center

Registration & Information Desk

C204

– 18 –

Sunday, 26 March　10:40 ～ 11:45 / 13:15 ～ 17:40 Plenary Lecture: Room B Tachibana Conference Hall, Sendai International Center (Conference building 2F) Invited Poster Presentation: Room G Meeting Room 4, Sendai International Center (Conference building 2F) 3rd International Symposium for Medicinal Sciences

10:40～ 10:45 Opening Remark � Chairman:�Akira�OTAKA（Tokushima�University）

10:45～ 11:45 Plenary Lecture 1 � Chairman:�Tsuneaki�SAKATA（Shionogi�&�Co.,�Ltd.）

ISMS-PL01 RobotScientists:AutomatingDrugDesignRoss�D.�KING（University�of�Manchester）

13:15～ 14:15 Plenary Lecture 2 � Chairman:�Tatsuhiko�KODAMA（The�University�of�Tokyo）

ISMS-PL02 RecentAdvancesincryo-EM:ApplicationstoDrugDiscoverySriram�SUBRAMANIAM（National�Cancer�Institute,�NIH）

14:20～ 17:40 Invited Poster Presentation

14:20 ～ 16:00 ShortPresentationforInvitedPosterPresentation16:00 ～ 17:40 PosterPresentation

DiscussionOddNumber:16:00 ～ 16:50EvenNumber:16:50 ～ 17:40

26G-ISMS01 UnstructuredProtein:ANewApproachforDrugDiscovery○Takenao�ODAGAMI1,�Yoichiro�HIROSE1,�Yoshimasa�IMAMURA1,�Akira�KATOH1,�Tadashi�MISHINA1,�Hiroyuki�KOUJI1（1Research�&�Development,�PRISM�BioLab�Co.,�Ltd.）

26G-ISMS02 DevelopmentofMacrocyclicPeptideTargetingEbolaGlycoprotein○ Shiori�UMEMOTO1,�Junki�MARUYAMA2,�Ayato�TAKADA2,�Hiroaki�SUGA1（1Department�of�Chemistry,�Graduate�School�of�Science,�The�University�of�Tokyo,�2Department�of�Global�Epidemiology,�Research�Center�for�Zoonosis�Control,�Hokkaido�University）

26G-ISMS03 CombinatorialSolid-PhaseSynthesisandBiologicalEvaluationofCyclodepsipeptideDestruxinBasaNegativeRegulatorforOsteoclastMorphology○Hiroshi�SATO1,2,�Masahito�YOSHIDA1,�Hayato�MURASE3,�Hiroshi�NAKAGAWA3,�Takayuki�DOI1（1Graduate�School�of�Pharmaceutical�Sciences,�Tohoku�University,�2Mitsubishi�Tanabe�Pharma�Corporation,�3�Department�of�Applied�Biological�Chemistry,�Chubu�University）

26G-ISMS04 SARExplorationofSelectiveKinaseInhibitorsbasedonthe“Head-to-Tail”Approach:DiscoveryofPI4KIIIαInhibitorsBearingDiverseScaffolds○ Satoru�NOJI1,�Noriyoshi�SEKI1,�Takaki�MAEBA1,�Takayuki�SAKAI1,�Eiichi�WATANABE1,�Katsuya�MAEDA1,�Kyoko�FUKUSHIMA1,�Toru�NOGUCHI1,�Kazuya�OGAWA1,�Yukiyo�TOYONAGA1,�Tamotsu�NEGORO1,�Hisashi�KAWASAKI1,�Makoto�SHIOZAKI1（1Central�Pharmaceutical�Research�Institute,�Japan�Tobacco�Inc.）

5 Program of 3rd International Symposium for Medicinal Sciences

– 19 –

26G-ISMS05 SearchforAnti-leukemicDrugsTargetingtheTranscriptionFactorRunx1byINTENDD○Masaaki�SHIINA1,�Shiho�BABA1,�Akiko�UCHIYAMA1,�Chikako�OKADA1,�Takeshi�TANAKA2,�Ken�IKEDA2,�Shigetsugu�KAWAKITA2,�Takao�MATSUZAKI2,�Hirotsugu�KOMATSU2,�Masato�HOSODA2,�Kazuhiro�OGATA1（1Yokohama�City�University,�Graduate�School�of�Medicine,�2Interprotein�Corporation）

26G-ISMS06 EvaluationofNovelAnti-DengueCandidatesUsingInSilicoandInVitroApproaches○Yu-Shi�TIAN1,�Hitoshi�MATSUDA2,�Xinzhe�LIU2,�Norihito�KAWASHITA2,3,�Tatsuya�TAKAGI2,3（1Graduate�School�of�Information�Science�and�Technology,�Osaka�University,�2Graduate�School�of�Pharmaceutical�Sciences,�Osaka�University,�3�Graduate�School�of�Information�Science�and�Technology,�Osaka�University�Research�Institute�for�Microbial�Diseases）

26G-ISMS07 DevelopmentandConstructionofanOriginalCompoundLibraryforCNSDrugDiscovery:CombiningComputationalandWetDatatoEnhanceCNSDrug-likeness○Daiju�HASEGAWA1（1Medicinal�Chemistry,�Neurology�Tsukuba�Research�Department,�Discovery,�Medicine�Creation,�Neurology�Business�Group,�Eisai�Co.,�Lid.）

26G-ISMS08 Structure-basedDesign,Synthesis,andBiologicalEvaluationofImidazo[1,2-b]Pyridazine-basedp38MAPKinaseInhibitors○Akira�KAIEDA1,�Masashi�TAKAHASHI1,�Takafumi�TAKAI1,�Masayuki�GOTO1,�Takahiro�MIYAZAKI1,�Yuri�HORI1,�Satoko�UNNO1,�Tomohiro�KAWAMOTO1,�Toshimasa�TANAKA1,�Sachiko�ITONO1,�Terufumi�TAKAGI1,�Teruki�HAMADA1,�Mikio�SHIRASAKI1,�Kengo�OKADA1,�Gyorgy�SNELL2,�Ken�BRAGSTAD2,�Bi-Ching�SANG2,�Osamu�UCHIKAWA1,�Seiji�MIWATASHI1（1Takeda�Pharmaceutical�Company�Limited,�2Takeda�California,�Inc.）

26G-ISMS09 FlowChemistry:NewHorizonsinChemicalSpacefortheCreationofNextGenerationLibrariesDaniel�BLANCO-ANIA3,�Sagar�Ashok�GAWADE1,�Luuk�MAARTENSE1,�Roel�VERLEIJSDONK1,�Remco�MERKX2,�Huib�OVAA2,�Floris�RUTJES1,�Marjon�BOLSTER3,�Luc�ZWINKELS3,�Joeri�SCHEIDT3,�Pauline�van�MEURS3,�Jorg�BENNINGSHOF3,�○ Norimasa�MORITA3（1Radboud�University,�2Leiden�UMC�(Former�NKI),�3Mercachem）

26G-ISMS10 TransitionMetal-Free,Tryptophan-SelectiveBioconjugationofProteins○Kounosuke�OISAKI1,�Yohei�SEKI1,�Takashi�ISHIYAMA1,�Daisuke�SASAKI1,2,�Junpei�ABE1,�Yohei�SOHMA1,2,�Motomu�KANAI1,2（1Graduate�School�of�Pharmaceutical�Sciences,�The�University�of�Tokyo,�2JST,�ERATO�Kanai�Life�Science�Catalysis�Project）

26G-ISMS11 TotalSynthesisofHalichondrinAandC○Akihiko�YAMAMOTO1,�Atsushi�UEDA1,�Paul�BRÉMOND1,�Paolo�S.�TISENI1,�Daisuke�KATO1,�Yoshito�KISHI1（1Department�of�Chemistry�and�Chemical�Biology,�Harvard�University）

26G-ISMS12 ParallelFluorescentProbeSynthesisBasedontheLarge-scalePreparationofBODIPYFLPropionicAcid○Taisuke�KATOH1,�Masato�YOSHIKAWA1,�Takeshi�YAMAMOTO1,�Ryosuke�ARAI1,�Noriyuki�NII1,�Yoshihide�TOMATA1,�Shinkichi�SUZUKI1,�Ryoukichi�KOYAMA1,�Nobuyuki�NEGORO1,�Takatoshi�YOGO1（1Pharmaceutical�Research�Division,�Takeda�Pharmaceutical�Company,�Ltd）

26G-ISMS13 ImprovementinPharmacokineticsandInVivoActivityofSomatostatinbyChemicalGlycosylation○Hirofumi�OCHIAI1,�Jun�IGARASHI1,�Hayato�SAIJO1,�Takahiro�YAMAMOTO1,�Yuji�NISHIUCHI1,�Akio�KANATANI1,�Taiji�SHIMODA1（1GlyTech,�Inc.）

26G-ISMS14 DevelopmentofanOxidativeMizoroki-HeckReactionforLate-stageC-HFunctionalizationofComplexMoleculesandApplicationtoPharmaceuticalStudies○Kenji�WATANABE1,�Amrita�DAS1,�Takumi�KIMIJIMA1,�Tomohiro�YAMASHITA1,�Kazuhide�INOUE1,�Makoto�TSUDA1,�Takashi�OHSHIMA1（1Graduate�School�of�Pharmaceutical�Sciences,�Kyushu�University）

– 20 –

26G-ISMS15 FunctionalCharacterizationofAcetylcholineReceptorsinHumanHippocampus-DerivedNeurons○Kazuyuki�FUKUSHIMA1,�Kazuto�YAMAZAKI2,�Norimasa�MIYAMOTO3,�Kohei�SAWADA3（1Neurology�Tsukuba�Research�Department,�Discovery,�Medicine�Creation,�Neurology�Business�Group,�Eisai�Co.,�Ltd.,�2Technology�Cross�Point�Laboratory,�hhc�Data�Creation�Center,�Eisai�Co.,�Ltd.,�3Global�CV�Assessment,�BA�CFU,�Medicine�Development�Center,�Eisai�Co.,�Ltd.）

26G-ISMS16 AnalgesicEffectofNovel11 β -HSD1InhibitorASP3662anditsMechanismofActioninaSpinalNerveLigationModelofNeuropathicPain○Tetsuo�KISO1,�Toshihiro�SEKIZAWA1,�Mina�TSUKAMOTO1,�Junko�YARIMIZU1,�Shuichiro�KAKIMOTO1（1Drug�Discovery�Research,�Astellas�Pharma�Inc.）

26G-ISMS17 Atomic-ScaleInvestigationonAcetaminophenCrystalswithStableandMetastablePhasesbyFrequencyModulationAtomicForceMicroscopyinAqueousSolution○Naritaka�KOBAYASHI1,�Kazuki�OKANO2,�Yoichiro�MORI3,�Shun�FUKUKITA3,�Mihoko�MARUYAMA4,�Hiroaki�ADACHI3,5,�Kazufumi�TAKANO4,5,�Satoshi�MURAKAMI5,6,�Hiroyoshi�MATSUMURA5,7,�Tsuyoshi�INOUE3,5,�Masashi�YOSHIMURA5,8,�Yusuke�MORI3,5,�Seiichiro�NAKABAYASHI1,�Hiroshi�YOSHIKAWA1,3（1Graduate�School�of�Science�and�Engineering,�Saitama�University,�2Faculty�of�Science,�Saitama�University,�3Graduate�School�of�Engineering,�Osaka�University,�4Graduate�School�of�Life�and�Environmental�Sciences,�Kyoto�Prefectural�University,�5SOSHO,�Inc.,�6Graduate�School�of�Bioscience�and�Biotechnology,�Tokyo�Institute�of�Technology,�7College�of�Life�Science,�Ritsumeikan�University,�8Institute�of�Laser�Engineering,�Osaka�University）

26G-ISMS18 Anti-inflammatoryFlavan-dihydrochalconeswithUnprecedentedCarbonSkeletonsfromDaemonoropsDraco○ Ping-Chung�KUO1,�Hsin-Yi�HUNG1,�Tsong-Long�HWANG2,�Tian-Shung�WU1（1�School�of�Pharmacy,�National�Cheng�Kung�University�Hospital,�College�of�Medicine,�National�Cheng�Kung�University,��2�Graduate�Institute�of�Natural�Products,�College�of�Medicine,�Chang�Gung�University）

26G-ISMS19 DevelopmentofaFullyAutomatedHPLCSystem(ASAPrepTM)DesignedforMultipleCompoundPurifications○Chie�KUSHIBE1,�Katsuhiko�MIWA1,�Hidetoshi�TERADA2,�Yuji�KATSUYAMA2（1Medicinal�Chemistry�Research�Laboratories,�Pharmaceutical�Research�Division,�Takeda�Pharmaceutical�Company�Limited,�2Life�Science�Business�Department,�Analytical�&�Measurement�Instruments�Division,�Shimadzu�Corporation）

26G-ISMS20 DiscoveryofaNovelPDE10AInhibitorasHighlyEffectiveforSchizophrenia○Yoichi�KADOH1,�Takehiko�MATSUMURA1,�Yoshihito�TANAKA1,�Mitsuya�HONGU1,�Haruko�MIYOSHI1,�Mayumi�KIMURA1,�Kei�TAKEDOMI1,�Kenji�OMORI1,�Jun�KOTERA1,�Takashi�SASAKI1,�Kiichi�TANAKA1,�Keiko�MIWA1,�Tamaki�KOBAYASHI1,�Hiroyuki�TANIGUCHI1,�Taketoshi�ISHII1,�Yumi�WATANABE1,�Haruna�ITODA1,�Rikiya�OHASHI1,�Kouki�KOJIMA1,�Masaya�FUKUDA1,�Saori�SATO1,�Itsuko�NAKAMURA1,�Toshiaki�SAKAMOTO1,�Toshiyuki�HIMIYAMA1,�Masataka�HIKOTA1,�Eiji�KAWANISHI1（1Mitsubishi�Tanabe�Pharma�Corporation）

26G-ISMS21 NucleicAcidDrugsLargeScaleManufacturingandSpecificationAssay–EquivalencySolidPhaseversusAJIPHASE®andOligonucleotideSequencesConfirmationforINDandNDA○ Satoshi�INOUE1,�Hirokazu�NANKAI1,�Emi�SAITO1,�Hideaki�SATO1,�Kazuhiko�YUYAMA1（1GeneDesign,�Inc.）

26G-ISMS22 Amycolamicin,aNovelAntibioticasaPromisingCandidateforClostridiumDifficileInfection:AntibacterialActivity,ModeofAction,andInVivoEfficacy○Yoshimasa�ISHIZAKI1,�Kazushige�SASAKI1,�Hideki�HASHIZUME1,�Chigusa�HAYASHI1,�Kunio�INOUE1,�Hayamitsu�ADACHI1,�Yoshiaki�TAKAHASHI1,�Masayuki�IGARASHI1,�Yoshio�NISHIMURA1,�Yuzuru�AKAMATSU1,�Akio�NOMOTO1,�Masakatsu�SHIBASAKI1（1Institute�of�Microbial�Chemistry�(BIKAKEN)）

26G-ISMS23 IdentificationandOptimizationofaNovelSeriesofTetrahydroisoquinolineDerivativesasanOrallyActiveMGAT2Inhibitor○Tsuyoshi�BUSUJIMA1,�Hiroaki�TANAKA2,�Eiji�MUNETOMO3,�Kiyokazu�KITANO3,�Masako�SAITO3（1Pharamceutical�Science�Laboratories,�2Chemistry�Laboratories,�3Pharmacology�Laboratories,�Taisho�Pharmaceutical�Co.,�Ltd.）

– 21 –

26G-ISMS24 DiscoveryofNovelFluoroquinoloneAntibioticsWFQ-101andItsOptimizationStudy○Tatsuya�HIRANO1,�Tomohiko�KINOSHITA1,�Daichi�KAZAMORI1,�Satoshi�INOUE1,�Kouji�NISHIMURA1,�Asuka�SAKURAI1,�Ayuka�SASAKI1,�Yasuhiro�KURAMOTO1,�Hirotaka�AMANO1,�Akira�YAZAKI1（1Drug�Discovery�Laboratory,�Wakunaga�Pharmaceutical�Co.,�Ltd.）

26G-ISMS25 Anti-CTLA-4AntibodyscFvProducingRecombinantBifidobacteriumSecretesCTLA-4BlockerSpecificallyInsideHypoxicTumorandSuppressesTumorGrowthinSyngeneicMiceModel○ Shiro�KATAOKA1,�Koichiro�SHIOYA1,�Li�WANG1,�Tomio�MATSUMURA1,�Hitomi�SHIMIZU1,�Yasuyoshi�KANARI1,�Yuji�SEKI1,�Yuko�SHIMATANI1,�Minoru�FUJIMORI2,�Shun'ichiro�TANIGUCHI3（1Anaeropharma�Science,�Inc.,�19-8,�Nihonbashi�Kabuto-cho,�Chuo-ku,�Tokyo�103-0026,�Japan,�2Department�of�Breast�Surgery,�Tokyo�Medical�University�Ibaraki�Medical�Center,�Ibaraki,�Japan,�3Department�of�Comprehensive�Cancer�Therapy,�Shinshu�University�School�of�Medicine）

26G-ISMS26 StructuralBasisforActivationofNeisseriaMeningitidesElongationFactorPwithArginine-32RhamnosylationbyEarP○Toru�SENGOKU1（1RIKEN�Structural�Biology�Laboratory）

26G-ISMS27 Design,SynthesisandBiologicalEvaluationofaNovelSeriesofPeripheral-selectiveNoradrenalineReuptakeInhibitor,PartI-LeadSeriesDiscoveryandBiologicalConceptValidation-○ Ikuo�FUJIMORI1,�Tomoya�YUKAWA1,�Taku�KAMEI1,�Yoshihisa�NAKADA1,�Nobuki�SAKAUCHI1,�Masami�YAMADA1,�Yusuke�OHBA1,�Maiko�TAKIGUCHI1,�Masako�KUNO1,�Izumi�KAMO1,�Hideyuki�NAKAGAWA1,�Teruki�HAMADA1,�Tomoko�IGARI1,�Teruaki�OKUDA1,�Satoshi�YAMAMOTO1,�Tetsuya�TSUKAMOTO1,�Yuji�ISHICHI1,�Hiroyuki�UENO1（1Takeda�Pharmaceutical�Company�Limited）

26G-ISMS28 Design,SynthesisandBiologicalEvaluationofaNovelSeriesofPeripheral-selectiveNoradrenalineReuptakeInhibitor,PartII-LeadOptimizationwithAvoidingP-gpSubstrateandGeneticPolymorphism-○Tomoya�YUKAWA1,�Ikuo�FUJIMORI1,�Taku�KAMEI1,�Yoshihisa�NAKADA1,�Nobuki�SAKAUCHI1,�Masami�YAMADA1,�Yusuke�OHBA1,�Hiroyuki�UENO1,�Maiko�TAKIGUCHI1,�Masako�KUNO1,�Izumi�KAMO1,�Hideyuki�NAKAGAWA1,�Yasushi�FUJIOKA1,�Tomoko�IGARI1,�Yuji�ISHICHI1,�Tetsuya�TSUKAMOTO1（1Takeda�Pharmaceutical�Company�Limited）

26G-ISMS29 ExVivoGene-manipulatedMatureAdipocytes:NovelGeneTherapyMedicineforSustainedProteinReplacementTherapyofVarietyofIntractableDiseases○Masayuki�KURODA1,�Hideaki�BUJO2,�Koutaro�YOKOTE3,�Yasushi�SAITO4,�Masayuki�ASO5（1Center�for�Advanced�Medicine,�Chiba�University,�2Department�of�Clinical�Laboratory�Medicine,�Toho�University�Medical�Center�Sakura�Hospital,�3Department�of�Clinical�Cell�Biology�and�Medicine,�Graduate�School�of�Medicine,�Chiba�University,�4Superintendent�of�the�hospital�bureau,�City�Hall�of�Chiba,�5CellGenTech,�Inc.）

26G-ISMS30 ApplicationofNovelHighlyImmunodeficientMiceforPatientDerivedXenograft(PDX)ModelandEvaluationofAnticancerTherapy○ Seiji�OKADA1,�Kulthida�VAETEEWOOTTACAHRN1,�Hiroki�GOTO1,�Ryusho�KARIYA1（1Center�for�AIDS�Research�and�Graduate�School�of�Medical�Sciences,�Kumamoto�University）

26G-ISMS31 TheUnboundConcentrationofMultimodalDrugsintheAssayMediumUsedintheMulti-electrodeArraySystemforCardiacRiskAssessmentwithiPSCell-derivedCardiomyocytes○Takashi�YOSHINAGA1,4,�Raku�SINKYO2,�Kiyomi�KIKUCHI2,�Tomohiko�TANIGUCHI1,4,�Yuko�SEKINO3,4,�Kohei�SAWADA1,4（1Global�CV�Assessment,�Eisai�Co.,�Ltd.,�2Global�DMPK,�Eisai�Co.,�Ltd.,�3Division�of�Pharmacology,�National�Institute�of�Health�Sciences,�4Japan�iPS�Cardiac�Safety�Assessment�(JiCSA)）

– 22 –

26G-ISMS32 DiscoveryofASP3026,aPotentandSelectiveAnaplasticLymphomaKinase(ALK)Inhibitor○Kazuhiko�IIKUBO1,�Yutaka�KONDOH1,�Itsuro�SHIMADA1,�Takahiro�MATSUYA1,�Kenichi�MORI1,�Yoko�UENO1,�Sadao�KUROMITSU1,�Minoru�OKADA1（1Astellas�Pharma�Inc.）

26G-ISMS33 ImmuneProfilingwithaNewNGS-basedRepertoireAnalysis○Takaji�MATSUTANI1,�Kazutaka�KITAURA1,�Hiroshi�YAMASHITA1,�Hitomi�AYABE1,�Hiroyuki�SATO1,�Yuichi�MORITA1,�Tadasu�SHINI2,3,�Ryuji�SUZUKI1,3（1Repertoire�Genesis�Incorporation,�2BITS.�Co.,�Ltd.,�3Clinical�Research�Center�for�Rheumatology�and�Allergy,�Sagamihara�National�Hospital）

26G-ISMS34 Cyclodextrin-basedSupramolecularDrugCarriersandActivePharmaceuticalIngredients○Taishi�HIGASHI1,�Keiichi�MOTOYAMA1,�Hidetoshi�ARIMA1,2（1Department�of�Physical�Pharmaceutics,�Graduate�School�of�Pharmaceutical�Sciences,�Kumamoto�University,�2Program�for�Leading�Graduate�Schools�“HIGO�(Health�life�science:�Interdisciplinary�and�Glocal�Oriented)�Program”,�Kumamoto�University）

26G-ISMS35 AntifungalActivitiesandNonclinicalPharmacokineticsofAPX001A/APX001(E1210/E1211),aNewBroad-SpectrumAntifungal,withaNewModeofAction○Takaaki�HORII1（1Global�Health�Research�Section,�hhc�Data�Creation�Center,�Eisai�Co.,�Ltd.）

26G-ISMS36 SynthesisandEvaluationofPotent,OrallyAvailable,Well-balancedEP2andEP3DualAgonists○Akihiro�KINOSHITA1,�Masato�HIGASHINO1,�Koji�YOSHIDA1,�Yoshiyuki�ARATANI1,�Akito�KAKUUCHI1,�Keisuke�HANADA1,�Hiroyuki�TAKEDA1,�Toshikiko�NISHIYAMA1,�Hidekazu�MATSUYA1,�Kazuyuki�OHMOTO1（1Medicinal�Chemistry�Research�Laboratories,�Ono�Pharmaceutical�Co.,�Ltd.）

26G-ISMS37 NovelDevelopmentofChemotherapyforRelapsedandRefractoryAMLBasedonthePromisingFunctionalMechanismofCytidineAnalog,DFP-10917○Masakazu�FUKUSHIMA1,�Kenzo�IIZUKA1,�Chung�ZHANG1,�Cheng�JIN1,�Kiyoshi�ESHIMA1（1Division�of�Research�and�Development,�Delta-Fly�Pharma,�Inc.）

26G-ISMS38 System-wideTemporalCharacterizationofthePhosphoproteomeofNon-small-cellLungCancerCellsTreatedwithErlotinib○Adachi�JUN1,�Yuichi�ABE1,�Maiko�SHIMIZU1,�Marina�KISHIDA1,�Ayako�SATO1,�Takeshi�TOMONAGA1（1Laboratory�of�Proteome�Research�National�Institutes�of�Biomedical�Innovation,�Health�and�Nutrition）

26G-ISMS39 IdentificationofWAC-224,aNovelAnticancerQuinoloneasaHumanTopoisomeraseIIInhibitor○Tomonori�YAMAGUCHI1,�Kenji�ITOH1,�Taichi�UESHIMA1,�Rumiko�SHIMABARA1,�Yohei�KAWAKUBO1,�Masayuki�SATO1,�Junpei�YAMASHITA1,�Tatsuya�HIRANO1,�Akira�YAZAKI1（1Drug�Discovery�Laboratory,�Wakunaga�Pharmaceutical�Co.,�Ltd.）

26G-ISMS40 LenvatinibMesilate(LEN)EnhancedAntitumorActivityofaPD-1BlockadeAgentbyPotentiatingTh1ImmuneResponse○Yu�KATO1,�Xingfeng�BAO2,�Shannon�MACGRATH2,�Kimiyo�TABATA1,�Yusaku�HORI1,�Sho�TACHINO1,�Mark�MATIJEVICI2,�Yasuhiro�FUNAHASHI1,�Junji�MATSUI1（1Eisai�Co.,�Ltd.,�Tsukuba,�Ibaraki,�Japan,�2Eisai�Inc.�Andover,�MA,�USA）

26G-ISMS41 IdentificationofBlood-basedGeneExpressionBiomarkersforMajorDepressiveandBipolarDisorders○ Seiji�NAKAMURA1,�Hiroaki�HORI2,�Yohei�ISHIZAWA1,�Kenichi�MATSUBARA1,�Ryo�MATOBA1,�Hiroshi�KUNUGI2（1DNA�Chip�Research�Inc.,�2Department�of�Mental�Disorder�Research,�National�Institute�of�Neuroscience,�National�Center�of�Neurology�and�Psychiatry）

– 23 –

26G-ISMS42 Anti-HelicobacterPyloriActivityofaNovelDerivativeofIntervenolin○Tomokazu�OHISHI1,�Toru�MASUDA1,�Shun-ichi�OHBA1,�Chigusa�HAYASHI2,�Hikaru�ABE3,�Masayuki�IGARASHI2,�Takumi�WATANABE3�,�Daniel�Ken�INAOKA4,�Kiyoshi�KITA5,�Masakatsu�SHIBASAKI3,�Manabu�KAWADA1,6（1Institute�of�Microbial�Chemistry�(BIKAKEN),�Numazu,�Microbial�Chemistry�Research�Foundation,�2Institute�of�Microbial�Chemistry�(BIKAKEN),�Laboratory�of�Microbiology,�Microbial�Chemistry�Research�Foundation,�3Institute�of�Microbial�Chemistry�(BIKAKEN),�Laboratory�of�Synthetic�Organic�Chemistry,�Microbial�Chemistry�Research�Foundation,�4Center�for�International�Collaborative�Research,�Nagasaki�University,�5School�of�Tropical�Medicine�and�Global�Health,�Nagasaki�University,�6Institute�of�Microbial�Chemistry�(BIKAKEN),�Laboratory�of�Oncology,�Microbial�Chemistry�Research�Foundation）

26G-ISMS43 DiscoveryofNovel5,6,7,8-tetrahydro[1,2,4]Triazolo[4,3-a]PyridineDerivativesasγ-secretaseModulators○Takafumi�TAKAI1,�Tatsuki�KOIKE1,�Minoru�NAKAMURA1,�Yasutaka�HOASHI1,�Yoshihide�TOMATA1,�Sachie�MORIMOTO1,�Yuichi�KAJITA1,�Toshiro�YAMASHITA1,�Naohiro�TAYA1,�Tetsuya�TSUKAMOTO1,�Tomomichi�WATANABE1,�Koji�MURAKAMI1,�Tomoko�IGARI1,�Makoto�KAMATA1（1Takeda�Pharmaceutical�Company�Limited）

26G-ISMS44 RegulatoryScienceforR&DPromotionofInnovativePharmaceuticals*Kazuhiko�MORI1,�Takao�YAMORI2,�○ Toru�KAWANISHI3,�Takao�INOUE4（1Ministry�of�Health,�Labor�and�Welfare�(MHLW),�2Pharmaceuticals�and�Medical�Devices�Agency�(PMDA),�3National�Institute�of�Health�Sciences�(NIHS),�4Japan�Agency�Medical�Research�and�Development�(AMED)）

– 24 –

ISMS-PL01 Robot Scientists: Automating Drug Design Ross D. KING

University of Manchester

A Robot Scientist is a physically implemented robotic system that applies techniques from artificial intelligence to execute cycles of automated scientific experimentation. A Robot Scientist can automatically execute cycles of: hypothesis formation, selection of efficient experiments to discriminate between hypotheses, execution of experiments using laboratory automation equipment, and analysis of results. The motivation for developing Robot Scientists is to better understand science, and to make scientific research more efficient. The Robot Scientist ‘Adam’ was the first machine to autonomously discover novel scientific knowledge. Our new Robot Scientist, ‘Eve’, is designed to automate and integrate drug screening, hit conformation, and QSAR development. Its combination of novel automation with synthetic biology assays enables faster and cheaper drug design. Eve’s focus was originally on neglected tropical diseases, and Eve has discovered hits and leads against targets in multiple parasites. We are now adapting Eve to work with and learn about human cancer cell lines. There is currently a ‘replication crisis’ in biology, and many scientific results have been shown to difficult to replicate. We argue that the formalisation of protocols, combined with the automation of experiments, is the best way to replicate results.

3rd International Symposium for Medicinal Sciences Akira OTAKA

Institute of Biomedical Sciences and Graduate School of Pharmaceutical　Sciences, Tokushima University

The objectives of this symposium are to encourage pharmaceutical company researchers who are interested in drug discovery to participate in this annual meeting, and also to create an important international platform for all those interested in the medicinal sciences. Since this symposium covers the entire drug discovery field, we welcome participants from disciplines including pharmacology, pharmacokinetics, and regulatory sciences.

One of the features of this symposium is a wide array of invited poster presentations. Since the program will include high-caliber presentations from the Japanese and foreign pharmaceutical industries, venture companies, and academia, young Japanese researchers who are interested in drug discovery will have valuable opportunities for discussion with first-class drug discovery researchers from around the world.

6 Abstracts

Plenary Lecture 1 Tachibana Conference Hall 10:45−11:45

– 25 –

ISMS-PL02 Recent Advances in cryo-EM: Applications to Drug Discovery Sriram SUBRAMANIAM

National Cancer Institute, NIH

Recent breakthroughs in the field of cryo-electron microcopy (cryo-EM) provide new prospects for determination of the structures of a variety of macromolecular assemblies and offer unprecedented opportunities for drug discovery. The prospect that the determination of protein structures to atomic resolution will no longer be limited by size, or by the need for crystallization represents a significant and exciting horizon in structural biology. I will discuss the application of these methods to analyze structures of a variety of biologically and medically relevant multi-protein complexes and membrane protein assemblies, which have historically represented the most challenging frontier in structural biology.Selected publications:• Merk A., Bartesaghi A, Banerjee S, Falconieri V, Rao P, Davis M, Pragani R, Boxer M, Earl LA, Milne JLS, Subramaniam S (2016) Breaking cryo-EM resolution barriers to facilitate drug discovery. Cell , 165 1698-1707.• Matthies D, Dalmas, O, Borgnia, MJ, Dominik, PK, Merk, A, Rao, P, Reddy, BG, Islam, S., Bartesaghi, A, Perozo, E, Subramaniam, S (2016) Cryo-EM Structures of the Magnesium Channel CorA Reveal Symmetry Break Upon Gating. Cell , 164, 747-756.• Banerjee, S, Bartesaghi, A, Merk, A, Rao, P. Bulfer, SL, Yan, Y, Green, N, Mroczkowski, B, Neitz, RJ, Wipf, P, Falconieri, V, Deshaies, RJ, Milne, JLS, Huryn D, Arkin, M, Subramaniam S (2016) 2.3 Å resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition. Science , 351,871-875.• Meyerson JR, Chittori S, Merk A, Rao P, Han TH, Serpe, M, Mayer ML, Subramaniam S (2016) Structural basis of kainate subtype glutamate receptor desensitization. Nature 537:567-571.• Bartesaghi A, Merk A, Banerjee S, Matthies D, Wu X, Milne JLS, Subramaniam S (2015) 2.2 Å resolution cryo-EM structure of β -galactosidase in complex with a cell-permeant inhibitor. Science 348:1147-1151.

Plenary Lecture 2 Tachibana Conference Hall 13:15−14:15

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26G-ISMS02 Development of Macrocyclic Peptide Targeting Ebola Glycoprotein ○ Shiori UMEMOTO1, Junki MARUYAMA2, Ayato TAKADA2, Hiroaki SUGA1

1Department of Chemistry, Graduate School of Science, The University of Tokyo, 2Department of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University

Ebola virus (EBOV), a member of the filovirus family, causes severe hemorrhagic fevers with 50-90% lethality. The EVOV glycoprotein (GP) is the sole virally expressed protein on the virion surface and is essential for attachment to the host cell and for membrane fusion. Hence, the EBOV GP is a critical drug target for combatting ebola virus. However, a truncated GP variant (sGP) that is secreted from infected cells may act as a decoy for drug candidate. As a result, high affinity and specificity, such as an antibody, is required for any drug targeting EBOV. We have previously developed a system, known as the RaPID system, to evolve macrocyclic peptides that specifically and strongly bind to a target protein and regulate function of the protein. The RaPID system combines ribosomal expression of a peptide library including non-proteogenic amino acids with ribosomal display, allowing expression of vast macrocyclic peptide libraries of up to trillions of macrocyclic peptides. In this poster, we introduce our strategy to develop macrocyclic peptides that bind to EBOV GP, the most potent of which has a dissociation constant of 6.3 nM, which is comparable of that of an antibody. The small size and potency of these macrocyclic peptides will give a big advantage in choice of strategies for functionalization, as well as easier handling and large scale production. They may therefore open up new strategy to combat EBOV.

26G-ISMS01 Unstructured Protein : A New Approach for Drug Discovery ○ Takenao ODAGAMI1, Yoichiro HIROSE1, Yoshimasa IMAMURA1, Akira KATOH1,

Tadashi MISHINA1, Hiroyuki KOUJI1

1Research & Development, PRISM BioLab Co., Ltd.

There are many successful examples in drug discovery of developing enzyme inhibitors and receptor agonists/antagonists. However, attempts to develop modulators of protein/protein interaction have largely been unsuccessful. This is especially true in developing modulators for transcription factors and for doing so with small molecules. Helix structures are prevalent and are often observed in intracellular protein/protein interactions. PRISM has designed novel compounds based on helix structures and has developed small to middle size molecules exhibiting strong activity in modulating critical intracellular protein/protein interaction. In case of intracellular protein/protein interaction, unstructured (intrinsic disorder) region plays an important role for their binding. The 50% of intracellular protein was estimated to have unstructured region. Intrinsic disorder region is highly abundant among proteins associated with various human diseases such as cancer, metabolic diseases, and cardiovascular diseases. However, systematic approach to target unstructured/structured protein/protein interaction has not been done in drug discovery area, to the best of our knowledge. PRISM focused on the protein/protein interaction to explore drug candidates. PRISM platform has resulted in a clinical-stage program based on targeting the CBP/beta-catenin complex, as well as other preclinical drug development programs. We would like to discuss here PRISM’s platform technology that focused on unstructured/structured protein/protein interaction to explore drug candidates.

Invited Poster Presentation Short Presentation Tachibana Conference Hall 14:20−16:00 Discussion Meeting Room 4 Odd Number: 16:00−16:50 / Even Number: 16:50−17:40

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26G-ISMS04 SAR Exploration of Selective Kinase Inhibitors based on the “Head-to-Tail” Approach: Discovery of PI4KIIIα Inhibitors Bearing Diverse Scaffolds

○ Satoru NOJI1, Noriyoshi SEKI1, Takaki MAEBA1, Takayuki SAKAI1, Eiichi WATANABE1, Katsuya MAEDA1, Kyoko FUKUSHIMA1, Toru NOGUCHI1, Kazuya OGAWA1, Yukiyo TOYONAGA1, Tamotsu NEGORO1, Hisashi KAWASAKI1, Makoto SHIOZAKI1

1Central Pharmaceutical Research Institute, Japan Tobacco Inc.

In typical kinase inhibitor programs, a hinge binder showing best potency with preferential specificity is initially selected, followed by fine-tuning of the accompanying substituents on its core module. A shortcoming of this approach is that the exclusive focus on a single chemotype can endanger all the analogues in the series if a critical drawback is revealed. Thus, an early effort to prepare such a potential risk by having a multiple series of compounds is rationalized, although there have been very few examples to follow such a policy. PI4KIIIα is one of four mammalian phosphatidylinositol-4 kinases and has recently drawn significant attention as an emerging target for hepatitis C virus (HCV) treatment. Inhibition of this host factor seems to provide a higher barrier to vial resistance as well as activity against all existing HCV genotypes. In this presentation, a novel “Head-to-Tail” approach to discover a diverse set of PI4KIIIα inhibitors is reported. We believe this method will generate distinct core scaffolds, a rational strategy to circumvent potential risks in general kinase programs.

26G-ISMS03 Combinatorial Solid-Phase Synthesis and Biological Evaluation of Cyclodepsipeptide Destruxin B as a Negative Regulator for Osteoclast Morphology

○ Hiroshi SATO1,2, Masahito YOSHIDA1, Hayato MURASE3, Hiroshi NAKAGAWA3, Takayuki DOI1

1Graduate School of Pharmaceutical Sciences, Tohoku University, 2Mitsubishi Tanabe Pharma Corporation, 3 Department of Applied Biological Chemistry, Chubu University

Cyclodepsipeptide destruxins were firstly isolated from Metarhizium anisopliae , and consist of five amino acids (β-Ala, L-MeAla, L-MeVal, L-Ile, and L-Pro) and an α-hydroxy acid derivative.1 In particular, destruxin B (1) that possesses an isobutyl moiety as a side-chain on an α-hydroxy acid derivative, reversibly inhibits bone-resorbing activity of osteoclasts without affecting cell viability.2 Therefore, destruxins can be a promising candidate for developing novel anti-resorptive agents. Because of structural and biological properties of 1, combinatorial synthesis and biological evaluation of cyclodepsipeptide destruxin B (1) were demonstrated.3 We designed 64-member analogues toward elucidation of structure-activity relationships, and the cyclization precursors were readily prepared by solid-phase peptide synthesis using a split and pool method. After cleavage from the polymer-support, macrolactonization utilizing MNBA-DMAPO in the solution phase was successfully performed in parallel to afford desired destruxin analogues in moderate to good yields. In this presentation, details of combinatorial synthesis and biological evaluation of the synthesized analogues will be discussed. References1. Païs, M.; Das, B. C.; Ferron, P. Phytochemistry 1981, 20, 715－ 723.2. Nakagawa, H.; Takami, M.; Udagawa, N.; Sawae, Y.; Suda, K.; Sasaki, T.; Takahashi, N.; Wachi, M.; Nagai, K.; Woo, J. T. Bone 2003, 33, 443－ 455.3. Sato, H.; Yoshida, M.; Murase, H.; Nakagawa, H.; Doi, T. ACS Comb. Sci, 2016, 18, 590-595.

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26G-ISMS06 Evaluation of Novel Anti-Dengue Candidates Using In Silico and In Vitro Approaches

○ Yu-Shi TIAN1, Hitoshi MATSUDA2, Xinzhe LIU2, Norihito KAWASHITA2,3, Tatsuya TAKAGI2,3

1Graduate School of Information Science and Technology, Osaka University, 2Graduate School of Pharmaceutical Sciences, Osaka University, 3 Graduate School of Information Science and Technology, Osaka University Research Institute for Microbial Diseases

Dengue virus or DENV belongs to the family Flaviviridae and is mediated by mosquitoes. Most patients appear in tropical and sub-tropical regions. Recently due to the climate change and the increase of global travelers, the regions of DENV infections are no more limited and being enlarged. The infections accompanying with hemorrhagic fever and/or shock syndrome became serious issues, especially when patients were infected by a different serotype of DENV for the second time. Although fruity studies on DENV have been carried out, so far no potent vaccine or antiviral drug has been approved [1]. We reported SK-12 in 2013 as a novel active molecule which is considered to target the interaction between non-structured viral proteins NS2B and NS3 [2]. In the current study, we look back into NS3/NS2B protease, a famous target for anti-Dengue study. We used high-throughput screening technique and In Silico studies to search for active candidates from compound libraries obtained from Osaka University. We found several candidates showed anti-DENV activities. Subsequently, these compounds were carefully checked to compare with previously reported molecules. Based on the most promising candidate, a screening of novel commercial libraries were carried out to solve time consume. We will present our results in the poster section and are looking afford for deep discussions. [1] (One example) Lai H. et al . Bioorg. Med. Chem. 21 102–113 2013.[2] Pambudi S. et al . Biochem. Biophys. Res. Commun. 440(3) 393-398 2013.

26G-ISMS05 Search for Anti-leukemic Drugs Targeting the Transcription Factor Runx1 by INTENDD

○Masaaki SHIINA1, Shiho BABA1, Akiko UCHIYAMA1, Chikako OKADA1, Takeshi TANAKA2, Ken IKEDA2, Shigetsugu KAWAKITA2, Takao MATSUZAKI2, Hirotsugu KOMATSU2, Masato HOSODA2, Kazuhiro OGATA1

1Yokohama City University, Graduate School of Medicine, 2Interprotein Corporation

Advance in the molecular targeted therapy has dramatically changed and improved a treatment of cancer. However, its narrow target spectrum and acquired drug resistance in tumors remain to be solved. These problems partly stem from the limited variation of the targeted molecules; almost all have been protein kinases. To settle the problems, a promising way is to develop drugs targeting proteins other than kinases. One of the potential targets is a transcription factor because its mutation is known to be frequently involved in cancer development. However, transcription factors do not have any enzymatic activity themselves, and thus the compounds necessarily target the molecular interactions involved, which is quite challenging. This may explain why few drugs targeting transcription factors have been available as long as we know. Our present research goal is to develop anti-leukemic drugs targeting a transcription factor, Runx1. Runx1 is known as a master regulator of the blood cell development, and various mutations of Runx1 gene have frequently been found in acute myeloblastic leukemia (AML) patients, leading to belief that Runx1 is an assured drug target for AML. Because Runx1 binds target gene enhancers as a heterodimer with CBFβ to regulate transcription, the desired compounds are likely to target the interactions of Runx1 with DNA or CBFβ . We started our challenge with a unique type of in silico screening, INTENDD, which was developed by INTEPROTEIN CORP. and stands for INTerprotein’s Engine for New Drug Design. In this method, we eyeball a real 3D model produced by a 3D printer based on a protein structure to find a molecular pocket for small compounds. Then, in silico screening is performed just for the candidate pockets. With INTENDD, we found and picked up 167 and 142 compounds targeting Runx1-DNA and Runx1-CBFβ interactions, respectively. Then we evaluated the inhibitory activity of the found compounds against DNA binding of Runx1 using surface plasmon resonance (SPR). We had totally 49 positive compounds, 3 of which strongly inhibited DNA binding of Runx1 with IC50 below 1 µM. We have verified that some of the positive compounds bind to Runx1 with the comparable affinity (KD: 0.01-10 µM range).

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26G-ISMS08 Structure-based Design, Synthesis, and Biological Evaluation of Imidazo[1,2-b]Pyridazine- based p38 MAP Kinase Inhibitors

○ Akira KAIEDA1, Masashi TAKAHASHI1, Takafumi TAKAI1, Masayuki GOTO1, Takahiro MIYAZAKI1, Yuri HORI1, Satoko UNNO1, Tomohiro KAWAMOTO1, Toshimasa TANAKA1, Sachiko ITONO1, Terufumi TAKAGI1, Teruki HAMADA1, Mikio SHIRASAKI1, Kengo OKADA1, Gyorgy SNELL2, Ken BRAGSTAD2, Bi-Ching SANG2, Osamu UCHIKAWA1, Seiji MIWATASHI1

1Takeda Pharmaceutical Company Limited, 2Takeda California, Inc.

We have identified a novel series of potent p38 MAP kinase inhibitors through structure-based design strategy. In the X-ray co-crystal structure of p38 MAP kinase with TAK-715 (1), Phe169 adopts two conformations that one interacts with 1 and the other shows no interaction with 1. Our structure-based design strategy is that these two conformations converge on one conformation by enhancement of the protein-ligand hydrophobic interaction. Scaffold transformation was conducted to enhance the protein-ligand hydrophobic interaction to resulting in the identification of imidazo[1,2-b]pyridazine derivatives as a lead series of potent p38 MAP kinase inhibitors, followed by investigation of structure and DMPK profile relationship. We provide a rational design, synthesis, SAR studies, and biological studies of imidazo[1,2-b]pyridazine derivatives.

26G-ISMS07 Development and Construction of an Original Compound Library for CNS Drug Discovery: Combining Computational and Wet Data to Enhance CNS Drug-likeness

○ Daiju HASEGAWA1

1Medicinal Chemistry, Neurology Tsukuba Research Department, Discovery, Medicine Creation, Neurology Business Group, Eisai Co., Lid.

High quality HTS hits are important for drug discovery programs to accelerate medchem campaign to clinical candidate and improve the overall success rate in the drug development. To provide such high quality HTS hits, sophisticatedly designed compound libraries play an important role in HTS strategy. In addition, a compound library with enhanced CNS drug-likeness (good brain penetrability and good oral availability) should improve the productivity of drug discovery programs in the neuroscience area. Against this background, we have been constructing a CNS-focused compound library by: • Innovative design to improve the probability of the compounds reaching the CNS. • Extensive in vitro , in vivo and physicochemical characterization of library members to eliminate

structures with inherent liabilities. • Newly-designed compounds based on structurally novel scaffolds.In this poster, we describe our strategy for constructing a CNS-focused compound library utilizing the combination of a computational scoring system and in vitro/in vivo DMPK data. In addition, we also describe how we gathered our original scaffold collection to emphasize structural novelty in the library.

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26G-ISMS10 Transition Metal-Free, Tryptophan-Selective Bioconjugation of Proteins ○ Kounosuke OISAKI1, Yohei SEKI1, Takashi ISHIYAMA1, Daisuke SASAKI1,2,

Junpei ABE1, Yohei SOHMA1,2, Motomu KANAI1,2

1Graduate School of Pharmaceutical Sciences, The University of Tokyo, 2JST, ERATO Kanai Life Science Catalysis Project

Chemical modifications of native proteins can facilitate production of supernatural protein functions that are not easily accessible by complementary methods relying on genetic manipulations. Even though precise control over the chemo-, site, and modification-number selectivity in protein chemical conjugates with maintained structural integrity and homogeneity is highly important, it still represents a major challenge. The available toolbox of native protein conjugations does not contain satisfactory solutions to this challenge at present. In many cases, the conjugation sites are located at the side chains of lysine and cysteine residues. Despite recent improvements, these methods often afford unsatisfactory levels of selectivity with disintegrated higher-order structures. We report a transition metal-free method for tryptophan-selective bioconjugation of proteins that is based on an organoradical and operates under ambient conditions. This method exhibits low levels of cross-reactivity and leaves higher-order structures of the protein and various functional groups therein unaffected. The strategy to target less abundant amino acids contributes to the formation of structurally homogeneous conjugates, which may even be suitable for protein crystallography. The absence of toxic metals and biochemically incompatible conditions may thus easily find therapeutic applications.

26G-ISMS09 Flow Chemistry: New Horizons in Chemical Space for the Creation of Next Generation Libraries

Daniel BLANCO-ANIA3, Sagar Ashok GAWADE1, Luuk MAARTENSE1, Roel VERLEIJSDONK1, Remco MERKX2, Huib OVAA2, Floris RUTJES1, Marjon BOLSTER3, Luc ZWINKELS3, Joeri SCHEIDT3, Pauline van MEURS3, Jorg BENNINGSHOF3, ○ Norimasa MORITA3

1Radboud University, 2Leiden UMC (Former NKI), 3Mercachem

As a member of the European Lead Factory (ELF), Mercachem is responsible for generation, validation and production of libraries consisting of ~10,000 compounds from ~20 scaffolds per year. This poster presents two examples where continuous flow chemistry facilitated the synthesis of scaffolds (and their corresponding libraries) with limited accessibility in batch processes. First, a 700 membered imidazolidinone library was smoothly prepared by the generation and subsequent reduction of an unstable and explosive azide keyintermediate in flow. Secondly, photochemistry in flow enabled the construction of two conformationally restricted three-dimensional aminoketone scaffolds at large scale in unprecedented efficiency.

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26G-ISMS12 Parallel Fluorescent Probe Synthesis Based on the Large-scale Preparation of BODIPY FL Propionic Acid

○ Taisuke KATOH1, Masato YOSHIKAWA1, Takeshi YAMAMOTO1, Ryosuke ARAI1, Noriyuki NII1, Yoshihide TOMATA1, Shinkichi SUZUKI1, Ryoukichi KOYAMA1, Nobuyuki NEGORO1, Takatoshi YOGO1

1Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd

We describe a methodology for quick development of fluorescent probes with the desired potency for the target of interest by using a method of parallel synthesis, termed as Parallel Fluorescent Probe Synthesis (Parallel-FPS). BODIPY FL propionic acid 1 is a widely used fluorophore, but is an expensive reagent, which hinders its use in parallel synthesis. Optimization of a synthetic scheme enabled us to obtain 50 g of 1 in one batch. With this large quantity of 1 in hand, we performed Parallel-FPS of BODIPY FL-labeled ligands for estrogen related receptor-α (ERRα). An initial trial of the parallel synthesis with various linkers provided a potent ligand for ERRα (Reporter IC50 = 80 nM), demonstrating the usefulness of Parallel-FPS.

26G-ISMS11 Total Synthesis of Halichondrin A and C ○ Akihiko YAMAMOTO1, Atsushi UEDA1, Paul BRÉMOND1, Paolo S. TISENI1,

Daisuke KATO1, Yoshito KISHI1

1Department of Chemistry and Chemical Biology, Harvard University

The first total sythesis of Halichondrin A and C was achieved by utilizing multiple Cr-mediated coupling to form a new C-C bond*. Halichondrins A/C are C12- and C13-di-hydroxylated / C12-hydroxylated form of Halichondrin B, whose right-half substructure led to the antitumor drug Eribulin (Figure 1). The syntheses are highlighted by the construction of C8-C14 polycyclic ketal for both A and C (Figure 2).

* J. Am. Chem.Soc. 2014, 136, 5171-5176, J. Am. Chem.Soc. 2012, 134, 893－896

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26G-ISMS14 Development of an Oxidative Mizoroki-Heck Reaction for Late-stage C-H Functionalization of Complex Molecules and Application to Pharmaceutical Studies

○ Kenji WATANABE1, Amrita DAS1, Takumi KIMIJIMA1, Tomohiro YAMASHITA1, Kazuhide INOUE1, Makoto TSUDA1, Takashi OHSHIMA1

1Graduate School of Pharmaceutical Sciences, Kyushu University

Duloxetine, a serotonin and noradrenaline reuptake inhibitor, was recently found to inhibit P2X4 receptors in microglial cells, and reduce nerve injury-induced allodynia in rats.1) Therefore, chemical modification of duloxetine may lead to the development of a potent drug for treating neuropathic pain. To synthesize a variety of duloxetine derivatives in a highly efficient way, we adopted a late-stage C–H functionalization strategy. Our initial trials using conventional C–H activation methods, however, resulted in the elimination of the naphtoxy group of duloxetine by due to severe reaction conditions. Therefore, we focused on the development of a new C–H activation reaction proceeding under neutral and mild condition, and finally we achieved a selective olefination of the thienyl group of duloxetine through catalytic oxidative Mizoroki-Heck reaction using molecular oxygen as the terminal oxidant.2) Under the optimized reaction conditions, various alkenyl groups were introduced into duloxetine in a highly regioselective manner. The obtained products were further transformed to various duloxetine derivatives, some of which showed improved biologic activity. We further studied fundamental reactivity of the reaction against various electron-rich arenes and hetero-arenes, and applied to late-stage functionalizations of several natural and medicinal compounds to demonstrate the utility of the reaction for the construction of chemical libraries of complex molecules.1) Yamashita, T.; Yamamoto, S.; Zhang, J.; Kometani, M.; Tomiyama, D.; Kohno, K.; Tozaki-Saitoh, H.; Inoue, K.; Tsuda, M. PLOS ONE 2016, 11(10): e0165189. doi:10.1371/ journal.pone.0165189. 2) Manuscript in preparation.

26G-ISMS13 Improvement in Pharmacokinetics and In Vivo Activity of Somatostatin by Chemical Glycosylation

○ Hirofumi OCHIAI1, Jun IGARASHI1, Hayato SAIJO1, Takahiro YAMAMOTO1, Yuji NISHIUCHI1, Akio KANATANI1, Taiji SHIMODA1

1GlyTech, Inc.

Somatostatin is naturally occurring peptide hormone that inhibits the secretion of several hormones through the binding to five distinct receptor subtypes. Despite the wide variety of its activity, therapeutic indications of native somatostatin are limited due to its short plasma half-life. In the present study, we synthesized glycosylated somatostatin analogs by chemically attaching one to four complex type sialyloligosaccharide chain(s) to the somatostatin molecule. The plasma half-life was extended by approximately 10-fold by the attachment of a single glycan, and the half-lives were prolonged by increasing the number of attached glycans. A single glycan-attached somatostatin maintained a high affinity to all receptor subtypes as in the case of native somatostatin. Furthermore, the glycosylated somatostatin demonstrated an efficient inhibition of growth hormone release in rats. These results indicate that glycosylated somatostatin analogs could be a potent therapeutic drug candidate for several diseases where somatostatin receptor subtypes are closely involved.

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26G-ISMS16 Analgesic Effect of Novel 11β -HSD1 Inhibitor ASP3662 and its Mechanism of Action in a Spinal Nerve Ligation Model of Neuropathic Pain

○ Tetsuo KISO1, Toshihiro SEKIZAWA1, Mina TSUKAMOTO1, Junko YARIMIZU1, Shuichiro KAKIMOTO1

1Drug Discovery Research, Astellas Pharma Inc.

Glucocorticoids exert their effects via glucocorticoid receptors (GRs), and the central GR is reportedly involved in the mechanism of neuropathic pain. 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) is involved in the conversion of inactive glucocorticoids to active glucocorticoids and is expressed not only in peripheral tissues but also in the central nervous system (CNS), such as brain and spinal cord. However, what role̶if any̶11β-HSD1 plays in pain transmission remains unclear. ASP3662 is a novel 11β -HSD1 inhibitor discovered through our research. Here, we investigated the analgesic effect and mechanism of ASP3662 in a spinal nerve ligation (SNL) model of neuropathic pain in rats. In SNL model rats, the left L5 and L6 spinal nerves were tightly ligated with silk thread. For intrathecal administration, the catheter was inserted between the L5 and L6 vertebrae. In the microdialysis experiment, the spinal cord dialysis probe was passed transversely through the dorsal spinal cord via bilateral holes made through vertebra L1. The mechanical threshold was determined by the von Frey hair test. ASP3662 concentrations in plasma and brain were determined via liquid chromatography-tandem mass spectrometry. One week after spinal nerve ligation, mechanical thresholds of the operated-side hindpaw were clearly lower than those in the sham group (mechanical allodynia). Single oral doses of ASP3662 significantly ameliorated mechanical allodynia, with an ED50 value of 0.087 mg/kg at 2 h after administration. Intrathecally administered ASP3662 also alleviated mechanical allodynia. A pharmacokinetics study using SNL model rats revealed CNS penetration by this compound. In a microdialysis experiment, intraperitoneally administered corticosterone, the active glucocorticoid in rodents, significantly increased spinal glutamate concentrations in normal rats. Intraperitoneally administered 11-dehydrocorticosterone (11-DHC), the inactive glucocorticoid in rodents, significantly increased spinal glutamate concentrations in an SNL model but not in normal rats. ASP3662 significantly inhibited this 11-DHC-induced increase in glutamate. ASP3662 is a novel, CNS-penetrable 11β-HSD1 inhibitor which alleviates mechanical allodynia in SNL rats. These results suggest that this compound is a promising candidate for use in treating neuropathic pain. One site of action of ASP3662 is the spinal cord. This compound may block glucocorticoid-induced increases in spinal glutamate concentration in SNL model rats by inhibiting conversion of inactive glucocorticoids into active ones.

26G-ISMS15 Functional Characterization of Acetylcholine Receptors in Human Hippocampus-Derived Neurons

○ Kazuyuki FUKUSHIMA1, Kazuto YAMAZAKI2, Norimasa MIYAMOTO3, Kohei SAWADA3

1Neurology Tsukuba Research Department, Discovery, Medicine Creation, Neurology Business Group, Eisai Co., Ltd., 2Technology Cross Point Laboratory, hhc Data Creation Center, Eisai Co., Ltd., 3Global CV Assessment, BA CFU, Medicine Development Center, Eisai Co., Ltd.

Utilizing human cell models mimicking physiologically- and/or disease-relevant conditions is a key strategy to improve success rates in drug development. To apply the strategy to the CNS drug development, it is essential to obtain functional human neurons. As a tool to generate functional human neurons, we utilized human hippocampus-derived neural stem/progenitor cells (HIP-009 cells). We previously demonstrated that HIP-009 cells can differentiate into neurons expressing glutamate receptors functionally, and that they were applicable to assessment system of drug candidates for glutamate receptor-related neurological disorders including Alzheimer’s disease (AD). In addition to glutamate receptors, acetylcholine receptors (AChRs) are another target group for AD therapeutics. Here, we examined the potential to apply HIP-009 neurons to functional assessment of drug candidates targeting AChRs. qRT-PCR analysis revealed that expression of nicotinic (nAChR) and muscarinic acetylcholine receptor (mAChR)-related genes was upregulated after four-week differentiation. Ca2+ flux assays of HIP-009 neurons demonstrated that intracellular Ca2+ signals were increased by nicotine and muscarine, indicating that HIP-009 neurons expressed nAChRs and mAChRs functionally. We also pharmacologically investigated expression of each subtype by using subtype-selective compounds, and identified functional expression of α7 and α4β2 nAChRs, as well as M1 and M3 mAChRs. These results suggest that HIP-009 neurons are applicable to functional evaluation of drug candidates acting on AChRs for AD drug development.

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26G-ISMS18 Anti-inflammatory Flavan-dihydrochalcones with Unprecedented Carbon Skeletons from Daemonorops Draco

○ Ping-Chung KUO1, Hsin-Yi HUNG1, Tsong-Long HWANG2, Tian-Shung WU1

1 School of Pharmacy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 2 Graduate Institute of Natural Products, College of Medicine, Chang Gung University

Four flavan-dihydrochalcones with unprecedented carbon skeletons, dragonins A-D (1-4) were characterized from the traditional Chinese medicine Sanguis Draconis. The structures of 1-4 were elucidated by spectroscopic and spectrometric analyses. Compounds 1 and 2 exhibited significant inhibition of fMLP/CB induced superoxide anion generation and elastase release. These purified flavan-dihydrochalcones are potentially new leads for anti-inflammatory drug development.

26G-ISMS17 Atomic-Scale Investigation on Acetaminophen Crystals with Stable and Metastable Phases by Frequency Modulation Atomic Force Microscopy in Aqueous Solution

○ Naritaka KOBAYASHI1, Kazuki OKANO2, Yoichiro MORI3, Shun FUKUKITA3, Mihoko MARUYAMA4, Hiroaki ADACHI3,5, Kazufumi TAKANO4,5, Satoshi MURAKAMI5,6, Hiroyoshi MATSUMURA5,7, Tsuyoshi INOUE3,5, Masashi YOSHIMURA5,8, Yusuke MORI3,5, Seiichiro NAKABAYASHI1, Hiroshi YOSHIKAWA1,3

1Graduate School of Science and Engineering, Saitama University, 2Faculty of Science, Saitama University, 3Graduate School of Engineering, Osaka University, 4Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, 5SOSHO, Inc., 6Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 7College of Life Science, Ritsumeikan University, 8Institute of Laser Engineering, Osaka University

Selective crystallization methods of metastable phase of medicinal organic compounds have been being developed to improve bioavailability in pharmaceutical application. These crystals are often grown from liquid phase. Therefore, it is quite useful for acceleration of the development to understand atomic-scale processes at crystal-solution interfaces. Frequency modulation atomic force microscopy (FM-AFM) is a powerful tool that can image surface structures with atomic resolution in liquid. FM-AFM has recently enabled us to visualize water molecules localized at solid-liquid interfaces by measuring 3D force distribution. The water distribution is called as hydration structure, which plays important roles in crystal growth. We have been investigating atomic-scale surface processes of acetaminophen (paracetamol) crystals with stable (Form I, monoclinic) and metastable (Form II, orthorhombic) phases by home-built atomic-resolution FM-AFM. We succeeded in obtaining atomic resolution images of Form I and II by imaging during their dissolution in nearly-saturated solutions. This is the first demonstration of atomic resolution imaging of soluble metastable crystal. We also revealed subnanoscale hydration structures formed on the surfaces of Form I and II.

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26G-ISMS20 Discovery of a Novel PDE10A Inhibitor as Highly Effective for Schizophrenia ○ Yoichi KADOH1, Takehiko MATSUMURA1, Yoshihito TANAKA1, Mitsuya HONGU1,

Haruko MIYOSHI1, Mayumi KIMURA1, Kei TAKEDOMI1, Kenji OMORI1, Jun KOTERA1, Takashi SASAKI1, Kiichi TANAKA1, Keiko MIWA1, Tamaki KOBAYASHI1, Hiroyuki TANIGUCHI1, Taketoshi ISHII1, Yumi WATANABE1, Haruna ITODA1, Rikiya OHASHI1, Kouki KOJIMA1, Masaya FUKUDA1, Saori SATO1, Itsuko NAKAMURA1, Toshiaki SAKAMOTO1, Toshiyuki HIMIYAMA1, Masataka HIKOTA1, Eiji KAWANISHI1

1Mitsubishi Tanabe Pharma Corporation

Phosphodiesterase10A (PDE10A), a dual hydrolase of cAMP and cGMP, is highly expressed in striatal medium spiny neurons (MSN). Inhibition of PDE10A modulates the activity of MSN via the regulation of cAMP. Therefore PDE10A inhibitor is expected as a therapeutic method for schizophrenia. We transformed Avanafil 1 (PDE5 inhibitor) derivatives, and discovered compound 2 that had weak inhibitory activity against PDE10A. More conversion of compound 2 improved the metabolic stability and brain penetration, and dimethylaminoquinoxaline substituted compound 3 that attenuated conditioned avoidance responses (CAR) in rats was produced. We performed in-depth optimization, and successfully obtained stilbene compound 4. The compound was substituted with 3-methyl-7-fluoro quinoxaline substituents, and reduced genotoxicity and CYP inhibition.

26G-ISMS19 Development of a Fully Automated HPLC System (ASAPrepTM) Designed for Multiple Compound Purifications

○ Chie KUSHIBE1, Katsuhiko MIWA1, Hidetoshi TERADA2, Yuji KATSUYAMA2

1Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2Life Science Business Department, Analytical & Measurement Instruments Division, Shimadzu Corporation

An automated decision-making process enabling seamless transitioning from analytical to preparative scale has been developed in collaboration with Shimadzu to improve purification process by Reversed-Phase High-Performance Liquid Chromatography-Mass Spectrometry (RP-HPLC-MS). Our method scouting protocol is based on database mining of alternative conditions to identify profitable separation conditions, like acidic or neutral mobile phases. An intelligent data processing software, in particular “MS spectral purity” significantly improves accuracy of decision-making. This innovative system, named “ASAPrepTM (Automated Scale-up from Analytical to Preparative)” has just been released globally in August 2014 from Shimadzu. In this poster presentation, we will show the advantages of this system, while highlighting the novelty of the purification procedures compared to the existing technology.

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26G-ISMS22 Amycolamicin, a Novel Antibiotic as a Promising Candidate for Clostridium Difficile Infection: Antibacterial Activity, Mode of Action, and In Vivo Efficacy

○ Yoshimasa ISHIZAKI1, Kazushige SASAKI1, Hideki HASHIZUME1, Chigusa HAYASHI1, Kunio INOUE1, Hayamitsu ADACHI1, Yoshiaki TAKAHASHI1, Masayuki IGARASHI1, Yoshio NISHIMURA1, Yuzuru AKAMATSU1, Akio NOMOTO1, Masakatsu SHIBASAKI1

1Institute of Microbial Chemistry (BIKAKEN)

A novel antibiotic amycolamicin (AM) discovered from the culture broth of Amycolatopsis sp. MK575-fF5 was originally isolated as a drug which showed strong antibacterial activities against Gram-positive bacteria such as MRSA, VRE and PRSP. Mode of action study revealed that AM inhibited bacterial DNA gyrase with IC50 of 24.4 ng/ml, without cross-resistance to other inhibitors of DNA gyrase such as quinolones and aminocoumarins. By contrast, AM did not inhibit human DNA topoisomerase II. Additionally, AM showed particularly strong antibacterial activity against C. difficile grown anaerobically. The MIC90s (n=45) of AM, vancomycin, and fidaxomicin were 0.25, 1.0, 0.25 µg/ml, respectively. AM also showed strong antibacterial activity against 13 species of Clostridiales , some Bacteroidales and Enterococcus faecalis/faecium, whereas showed moderate or weak antibacterial activity against other enteric bacteria including Bifidobacteriales , Lactobacillales and some Bacteroidales . In a therapeutic experiment using for antibiotic- associated pseudomembranous colitis caused by C. difficile ATCC 43255 in hamsters, AM showed an equivalent therapeutic efficacy to fidaxomicin at 6, 20, and 60 mg/kg/day by oral administration (n=7). In conclusion, AM showed to possess strong activity against C. difficile with novel mechanism of action. The efficacy in hamster model for pseudomembranous colitis warrants further evaluation of AM.

26G-ISMS21 Nucleic Acid Drugs Large Scale Manufacturing and Specification Assay– Equivalency Solid Phase versus AJIPHASE® and Oligonucleotide Sequences Confirmation for IND and NDA

○ Satoshi INOUE1, Hirokazu NANKAI1, Emi SAITO1, Hideaki SATO1, Kazuhiko YUYAMA1

1GeneDesign, Inc.

Oligonucleotides which constitutes nucleic acid drug, are provided by chemical synthesis. We already have several track records of the GMP production of some nucleic acid drugs. All these batches were synthesized by solid phase synthesis which is well established organic chemistry but it is limited for scalability and cost effectivity. To overcome this issue, we have been co-developed liquid phase synthetic methodology of oligonucleotides called AJIPHASE® originated by AJINOMOTO. Comparison data between solid phase and AJIPHASE® showed that two methods are equivalent for impurity profile and purity. This result shows one of breakthrough of cost effective nucleic acid drug development. We believe nucleic acid drugs development is accelerated by AJIPHASE®. On the other hand, in the analysis of nucleic acid drugs for specification, sequence confirmation examination is critical test of identification. We show example of sequence confirmation examination using MS different methodologies. We can cope to IND and NDA by above-mentioned production technology and analysis technique.

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26G-ISMS24 Discovery of Novel Fluoroquinolone Antibiotics WFQ-101 and Its Optimization Study

○ Tatsuya HIRANO1, Tomohiko KINOSHITA1, Daichi KAZAMORI1, Satoshi INOUE1, Kouji NISHIMURA1, Asuka SAKURAI1, Ayuka SASAKI1, Yasuhiro KURAMOTO1, Hirotaka AMANO1, Akira YAZAKI1

1Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd.

As the difficult-to-treat infections caused by multidrug-resistant bacteria have spread, it is an urgent need to develop novel antibiotics for the treatment of them. Therefore, we started the research to discover novel antibiotics with potent antibacterial activities, especially against Gram-negative resistant pathogens. Recently, we evaluated the minimum inhibitory concentration (MIC) of our quinolone library for P. aeruginosa with or without the efflux pump inhibitor PAβN. We found that the MICs of a certain type of compounds such as WFQ-101, having 2-hydroxymethylphenyl group at 1-position, were less changed by the presence of PAβN, indicating the possibility to overcome the drug resistance by bacterial efflux system. We selected WFQ-101 as a lead compound and have continued its structural optimization. For example, an introduction of 5-methyl group drastically increased the activity, whereas the modification of 7-substituent, such as the increases of lipophilicity and/or bulkiness, was not tolerated for the activity against Gram-negative pathogens. In this presentation, we will describe the results of our optimization study, demonstrating the Structure-Activity Relationship.

26G-ISMS23 Identification and Optimization of a Novel Series of Tetrahydroisoquinoline Derivatives as an Orally Active MGAT2 Inhibitor

○ Tsuyoshi BUSUJIMA1, Hiroaki TANAKA2, Eiji MUNETOMO3, Kiyokazu KITANO3, Masako SAITO3

1Pharamceutical Science Laboratories, 2Chemistry Laboratories, 3Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd.

MGAT2 (monoacylglycerol acyltransferase 2) is expected to be an attractive target for the drug treatment of obesity, diabetes, and other disease. We describe our exploration and structure-activity relationship (SAR) study of 2,3-dihydro-1H-isoindole-5-sulfonamide derivatives which was derived from a hit compound identified by our high throughput screening campaign. In this study, we identified an orally available MGAT2 inhibitor through optimization in terms of solubility. This compound exhibited moderate potency in the enzyme inhibitory assay (IC50 = 1522 nM) and an in vivo efficacy at an oral dose of 100 mg/kg in a mouse oral lipid tolerance test.Further optimization of a novel series of 1,2,3,4-tetrahydroisoquinoline-6-sulfonamide derivatives to improve the intrinsic potency culminated in the identification of TP0455353, 2-[2-(4-tert-butylphenyl)ethyl]-N-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-1,2,3,4-tetrahydroiso-quinoline-6-sulfonamide, which was the most potent MGAT2 inhibitor among this series with an IC50 value of 28 nM. Oral administration of TP0455353 at a dose of 3 mg/kg in the oral lipid tolerance test resulted in significant suppression of triglyceride synthesis.

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26G-ISMS26 Structural Basis for Activation of Neisseria Meningitides Elongation Factor P with Arginine-32 Rhamnosylation by EarP

○ Toru SENGOKU1

1RIKEN Structural Biology Laboratory

Protein glycosylation is a universal post-translational modification regulating many cellular processes. The only known protein arginine rhamnosyltransferase, EarP, specifically rhamnosylates Arg32 of elongation factor P (EF-P). We report a crystallographic study of Neisseria meningitidis EarP. EarP binds the entire beta-sheet structure of domain I of EF-P, forming numerous interactions that specifically recognize its conserved sequences. This recognition mechanism, which is both structure- and sequence-specific, sharply contrasts with those of other known glycosyltransferases that accept substrates with different sizes and/or sequences. A molecular dynamics simulation suggested that the rhamnose moiety should change its conformation during the reaction. These insights should facilitate the development of new EarP inhibitors that target only EarP-containing pathogenic bacteria.

26G-ISMS25 Anti-CTLA-4 Antibody scFv Producing Recombinant Bifidobacterium Secretes CTLA-4 Blocker Specifically Inside Hypoxic Tumor and Suppresses Tumor Growth in Syngeneic Mice Model

○ Shiro KATAOKA1, Koichiro SHIOYA1, Li WANG1, Tomio MATSUMURA1, Hitomi SHIMIZU1, Yasuyoshi KANARI1, Yuji SEKI1, Yuko SHIMATANI1, Minoru FUJIMORI2, Shun’ichiro TANIGUCHI3

1Anaeropharma Science, Inc., 19-8, Nihonbashi Kabuto-cho, Chuo-ku, Tokyo 103-0026, Japan, 2Department of Breast Surgery, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan, 3Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine

Anti-PD-1 antibody and anti-CTLA-4 antibody showed notable efficacy and the combination complimentarily enhanced antitumor benefit. Nevertheless, either single-agent therapy or combination therapy is facing immune-related adverse events (irAEs), which are major cause of treatment discontinuation. Non-specific systemic activation of normal immune system by the therapy is one of major reasons to cause the problems. Approaches to increase the delivery of checkpoint blockers to tumor site may minimize the irAEs and improve the response rate in patients. In an aim to improve efficiency of anti-cancer drug delivery, we have been developing in situ Delivery and Production System (i-DPS) by modifying a non-pathogenic anaerobic bacterium, Bifidobacterium, which localizes and proliferates only in the hypoxic environment like solid tumors after I.V. administration and also produces anticancer proteins, enzymes or other pharmacologically active molecules selectively at the tumor site. Here we present anti-CTLA-4 antibody scFv producing i-DPS in cancer immunotherapy, which could be specifically delivered to and amplified only at the hypoxic sites of solid tumors.

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26G-ISMS28 Design, Synthesis and Biological Evaluation of a Novel Series of Peripheral-selective Noradrenaline Reuptake Inhibitor, Part II -Lead Optimization with Avoiding P-gp Substrate and Genetic Polymorphism-

○ Tomoya YUKAWA1, Ikuo FUJIMORI1, Taku KAMEI1, Yoshihisa NAKADA1, Nobuki SAKAUCHI1, Masami YAMADA1, Yusuke OHBA1, Hiroyuki UENO1, Maiko TAKIGUCHI1, Masako KUNO1, Izumi KAMO1, Hideyuki NAKAGAWA1, Yasushi FUJIOKA1, Tomoko IGARI1, Yuji ISHICHI1, Tetsuya TSUKAMOTO1

1Takeda Pharmaceutical Company Limited

Peripherally selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Herein, we describe our medicinal chemistry approach to discover peripheral-selective noradrenaline reuptake inhibitors to avert the risk of P-gp-mediated DDI at the blood–brain barrier. We observed that steric shielding of the HBA and HBD reduced the multidrug resistance protein 1 (MDR1) efflux ratio; however, the resulting compound was mainly metabolized by CYP2D6 and CYP2C19 in the in vitro phenotyping study, implying the risk of PK variability based on the genetic polymorphism. Replacement of the hydrogen atom with a deuterium atom in a strategic, metabolically hot spot led to compound, which was mainly metabolized by CYP3A4. To our knowledge, this study represents the first report of the effect of deuterium replacement for a major metabolic enzyme.

26G-ISMS27 Design, Synthesis and Biological Evaluation of a Novel Series of Peripheral-selective Noradrenaline Reuptake Inhibitor, Part I -Lead Series Discovery and Biological Concept Validation-

○ Ikuo FUJIMORI1, Tomoya YUKAWA1, Taku KAMEI1, Yoshihisa NAKADA1, Nobuki SAKAUCHI1, Masami YAMADA1, Yusuke OHBA1, Maiko TAKIGUCHI1, Masako KUNO1, Izumi KAMO1, Hideyuki NAKAGAWA1, Teruki HAMADA1, Tomoko IGARI1, Teruaki OKUDA1, Satoshi YAMAMOTO1, Tetsuya TSUKAMOTO1, Yuji ISHICHI1, Hiroyuki UENO1


Centrally acting noradrenaline reuptake inhibitor (NRI) is reportedly effective for patients with stress urinary incontinence (SUI) by increasing urethral closure in the clinical Phase IIa study with esreboxetine. Noradrenaline transporters are expressed in both central and peripheral nervous systems and the contribution of each site to efficacy has not been clarified. This poster describes the development of a series of peripheral-selective 7-phenyl-1,4-oxazepane NRIs to investigate the contribution of the peripheral site to increasing urethral resistance in rats. An acetamide derivative which showed high peripheral NET selectivity in rats increased urethral resistance in a dose-dependent manner and exhibited a maximal effect on par with esreboxetine. These results indicate that the urethral resistance-increasing effects of NRI in rats are fully achieved by the peripheral selective NET inhibition.

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26G-ISMS30 Application of Novel Highly Immunodeficient Mice for Patient Derived Xenograft (PDX) Model and Evaluation of Anticancer Therapy

○ Seiji OKADA1, Kulthida VAETEEWOOTTACAHRN1, Hiroki GOTO1, Ryusho KARIYA1

1Center for AIDS Research and Graduate School of Medical Sciences, Kumamoto University

Xenograft tumor models from patient-derived tumor tissue at low passage have been shown to conserve original tumor characteristics such as heterogeneous histology, clinical biomolecular signature, malignant phenotypes and genotypes, tumor architecture and tumor vasculature. Patient-derived tumor xenografts (PDX) are now believed to offer relevant predictive insights into clinical outcomes when evaluating the efficacy of novel cancer therapies. NOD/Scid based immunodeficient mice (ex. NOD/Scid, NOG, NSG, and NOJ mice) have been used as the recipient of human tumor transplantation due to the high forming efficiency, however, these mice are relatively weak, shorter life span and low breeding efficiency. We developed Balb/c Rag-1 Jak3 double deficient (Balb/c RJ) mice to cover these disadvantages. Breeding efficiency of Balb/c RJ mice are same as Balb/c mice and human hematopoietic cells and tumor cells are also successfully seeded and developed in Balb/c RJ mice. We transplanted patient derived cholangiocarcinoma (CCA) tissue into Balb/c RJ mice subcutaneously, and 16 out of 20 cases formed tumors in mice, and 4 CCA cell lines were established from PDX tissue culture. PDX model using Balb/c RJ mice can be the useful tool for cancer research and drug development.

26G-ISMS29 Ex Vivo Gene-manipulated Mature Adipocytes: Novel Gene Therapy Medicine for Sustained Protein Replacement Therapy of Variety of Intractable Diseases

○Masayuki KURODA1, Hideaki BUJO2, Koutaro YOKOTE3, Yasushi SAITO4, Masayuki ASO5

1Center for Advanced Medicine, Chiba University, 2Department of Clinical Laboratory Medicine, Toho University Medical Center Sakura Hospital, 3Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, 4Superintendent of the hospital bureau, City Hall of Chiba, 5CellGenTech, Inc.

Gene therapy-based protein replacement is one of absolute needs for treatment of inherited diseases. Based on much experiences of clinical transplantation therapy in cosmetic and reconstructive surgery, adipose tissue is now recognized as a source of proliferative cells for cell-based therapy. We have developed manipulation procedure of mature adipocytes through ceiling culture with subsequent retroviral/lentiviral gene transduction. The propagated cells, designated as ceiling culture-derived proliferative adipocytes (ccdPAs), provide efficient gene transduction efficiency with stable secretion of the transduced-gene products. GMP production procedure, by which the gene-transduced ccdPAs could be expanded up to nearly 1012 cells from 1 g of fat tissue for three weeks after fat tissue preparation, has been developed. The platform technology has been applied for ex vivo gene therapy of familial lecithin:cholesterol acyltransferase (LCAT) deficiency. Clinical first in human study for treatment of familial LCAT deficiency has been approved by Ministry of Health, Labour and Welfare, followed by initiation of patient enrollment in Japan. We further continue our research and development to obtain approval as gene therapy medicine. Thus, ccdPAs would provide an excellent platform for developing a protein replacement therapy not only for LCAT deficiency but also variety of intractable diseases including hemophilia and lysosomal storage diseases.

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26G-ISMS32 Discovery of ASP3026, a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor

○ Kazuhiko IIKUBO1, Yutaka KONDOH1, Itsuro SHIMADA1, Takahiro MATSUYA1, Kenichi MORI1, Yoko UENO1, Sadao KUROMITSU1, Minoru OKADA1

1Astellas Pharma Inc.

Anaplastic lymphoma kinase (ALK) is a promising therapeutic target for the treatment of cancers, including echinoderm microtubule-associated protein-like 4 (EML4)-ALK positive non-small cell lung cancer. We synthesized a series of 1,3,5-triazine derivatives and discovered ASP3026 as a potent and selective ALK inhibitor, which demonstrated dose-dependent antitumor activity in mice bearing NCI-H2228 tumor xenografts. ASP3026 also showed inhibitory activity against the L1196M gatekeeper mutant of ALK. Syntheses and structure-activity relationships of 1,3,5-triazine derivatives and computational modelings of ASP3026 will be presented.

26G-ISMS31 The Unbound Concentration of Multimodal Drugs in the Assay Medium Used in the Multi-electrode Array System for Cardiac Risk Assessment with iPS Cell-derived Cardiomyocytes

○ Takashi YOSHINAGA1,4, Raku SINKYO2, Kiyomi KIKUCHI2, Tomohiko TANIGUCHI1,4, Yuko SEKINO3,4, Kohei SAWADA1,4

1Global CV Assessment, Eisai Co., Ltd., 2Global DMPK, Eisai Co., Ltd., 3Division of Pharmacology, National Institute of Health Sciences, 4Japan iPS Cardiac Safety Assessment (JiCSA)

To characterize and predict the QT interval prolongation and proarrhythmia potential of drug candidates, investigations into the challenges of using multi-electrode array system and human stem cell-derived cardiomyocytes are on-going. Sometimes, discussions arise on whether assay results should be interpreted using total (applied) or unbound concentrations to understand the compounds cardiovascular liabilities. To provide useful suggestions, we measured the unbound concentrations of 59 drugs which include CiPA selected 29 compounds in the iCell Cardiomyocytes Maintenance Medium (CMM, Cellular Dynamics International) including fetal bovine serum by equilibrium dialysis method using Rapid Equilibrium Dialysis device (ThermoFisher Scientific). Then, unbound fraction (fu) values at low and high concentrations (100-fold differences) in CMM were calculated. When saturation of binding at the high concentration was observed, an additional experiment was done at a middle concentration. Most of compounds showed similar fu values at low and high concentrations. On the other hand, several compounds such as Mibefradil, Thioridazine, Bepridil, Prenylamine, Tolterodine, Haloperidol, and Dronedarone showed more than 2-fold higher fu values at high concentrations than those at low ones. Tamoxifene and Amiodarone showed very low fu values (less than 0.01) which indicated very strong protein binding. Further analysis of the relationships between the fu values in CMM and human plasma was conducted. Good correlation in rank order with non-linier correlation was obtained. These results indicated that the actual unbound concentrations in CMM will be very useful to consider and interpret the relationship to unbound plasma concentrations which caused CV events in human.

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26G-ISMS34 Cyclodextrin-based Supramolecular Drug Carriers and Active Pharmaceutical Ingredients

○ Taishi HIGASHI1, Keiichi MOTOYAMA1, Hidetoshi ARIMA1,2

1Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2Program for Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program”, Kumamoto University

Cyclodextrins (CyDs) are cyclic oligosaccharides composed of six (α-CyD), seven (β-CyD), and eight (γ-CyD) glucopyranose units that can form inclusion complexes with various organic and inorganic compounds. Recently, we have developed CyD-based supramolecular drug carriers for low-molecular weight drugs, peptide/protein drugs, gene and nucleic acid drugs through the combination with functional polymers or macromolecules, such as dendrimer, polyethylene glycol (PEG) and liposome (Fig. 1). Moreover, we also utilized CyDs as active pharmaceutical ingredients. In this presentation, we introduce the recent applications of CyDs as drug carriers and active pharmaceutical ingredients. The topics of the presentation are shown as follows.

1) Folate-appended CyDs as drug carriers for low-molecular weight anticancer drugs

2) Reversible PEGylation for peptide/protein drugs based on CyD/adamantane interaction

3) Polypseudorotaxane hydrogels as a stabilizer for antibodies4) Ligand-appended dendrimer/CyD conjugates as gene and

nucleic acid drugs carriers5) Folate-appended CyDs as tumor-selective anticancer drugs

26G-ISMS33 Immune Profiling with a New NGS-based Repertoire Analysis ○ Takaji MATSUTANI1, Kazutaka KITAURA1, Hiroshi YAMASHITA1, Hitomi AYABE1,

Hiroyuki SATO1, Yuichi MORITA1, Tadasu SHINI2,3, Ryuji SUZUKI1,3

1Repertoire Genesis Incorporation, 2BITS. Co., Ltd., 3Clinical Research Center for Rheumatology and Allergy, Sagamihara National Hospital

NGS-based TCR and BCR repertoire analyses are powerful tools to analyze specificities and diversities of T and B cells. Here, we developed a new TCR/BCR repertoire analysis methods using unbiased amplification (adaptor-ligation PCR) and an in-house developed analysis software following a paired-end MiSeq sequencing. This method enables a highly accurate and quantitative analysis. With regard to TCR, we examined gene usage, diversity and similarity of TRA/TRB repertoires with PBMCs of 20 healthy individuals. TRA repertoires were more similar between individuals than TRB repertoires were. The inter-individual similarity of TRA depended largely on the frequent presence of shared TCRs among two or more individuals. The shared TRA sequences often contained invariant TCRα derived from invariant natural killer T (iNKT) and mucosa-associated invariant T (MAIT) cells. Regarding BCR, we sequenced five isotypes of IgH (IgM, IgD, IgG, IgA and IgE) in 12 individuals and analyzed frequencies of somatic hypermutation (SHM) among Ig subclasses. Shared sequences were frequently observed within multiple Ig subclasses and the frequency of SHM varied among the Ig subclasses. Respite the sequential class-switch recombination (CSR) from upstream to downstream subclasses, the shared clones had the almost same SHM levels while subclass-specific clones had a different levels of SHM dependent of genomic location. These results gave us an interesting insight into the development and the maturation of B cells. In conclusion, NGS-based TCR/BCR repertoire analysis will provide us critical information on T and B cells playing a pivotal role in immune system.

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26G-ISMS36 Synthesis and Evaluation of Potent, Orally Available, Well-balanced EP2 and EP3 Dual Agonists

○ Akihiro KINOSHITA1, Masato HIGASHINO1, Koji YOSHIDA1, Yoshiyuki ARATANI1, Akito KAKUUCHI1, Keisuke HANADA1, Hiroyuki TAKEDA1, Toshikiko NISHIYAMA1, Hidekazu MATSUYA1, Kazuyuki OHMOTO1

1Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd.

Our purpose was to develop PGE2 analogs possessing highly potent dual EP2 and EP3 agonist activity with selectivity against the other two subtypes (EP1 and EP4), because a dual EP2 and EP3 agonist is expected as an effective therapeutics addressing unmet medical needs for treatment of a underactive bladder (UAB). While no dual EP2 and EP3 agonist has been reported, a dual EP2 and EP4 agonist with selectivity against the EP1 and EP3 receptor subtypes was reported in 20121. At first, we synthesized cyclic carbamate derivatives having cyclobutyl group and terminal fluorine atom in order to reduce EP4 agonist activity and add EP3 agonist activity, and then replaced the core structure with cyclopentanone for enhancement of orally absorption. The resulting compound, ONO-8055, showed excellent potency (human EC50 EP2 = 0.67 nM，EP3 = 0.7 nM), EP1 and EP4 subtype selectivity (>400-fold) and good pharmacokinetic profiles. Regarding in vivo efficacy, ONO-8055 improved the lower urinary tract dysfunctions of neurogenic underactive bladder in a rat lumber spinal stenosis (LCS) model2. Furthermore, as a result of Phase I trial in Europe, there was no safety or PK concern. ONO-8055 is currently under development as a new highly promising UAB drug.1) Kambe, T.; Maruyama, T; Nakai, Y; Oida H.; Maruyama T.; Abe N.; Nishiura, A.; Nakai, H.; Toda, M.

Bioorganic & Medicinal Chemistry, 2012, 20, 3502.2) Sekido N.; Kida J.; Mashimo H.; Wakamatsu D.; Okada H.; Matsuya H.; J Urol, 2016, 196, 609.

26G-ISMS35 Antifungal Activities and Nonclinical Pharmacokinetics of APX001A/APX001 (E1210/E1211), a New Broad-Spectrum Antifungal, with a New Mode of Action

○ Takaaki HORII1

1Global Health Research Section, hhc Data Creation Center, Eisai Co., Ltd.

APX001A (formerly known as E1210) inhibited the inositol acylation of fungus-specific glycosylphosphatidylinositol (GPI), which is catalyzed by Gwt1p, leading to the inhibition of GPI-anchored protein maturation. The compound not only inhibited fungal growth, but also suppressed the expression of some virulence factors of fungi. APX001A demonstrated potent, broad-spectrum antifungal activity against clinically important fungi, including Candida spp., Aspergillus spp., and other filamentous fungi. It showed no cross-resistance with azoles and echinocandins. APX001 (formerly known as E1211) is a water-soluble prodrug of APX001A, and efficiently converted to APX001A in animals, and in human S9 tissue fractions in vitro. APX001 was effective in murine models of candidiasis, aspergillosis, fusariosis, and scedosporiosis. Furthermore, APX001/ APX001A demonstrated synergy in combination with other antifungals in vitro and in vivo against Candida spp. and Aspergillus spp. Amplyx Pharmaceuticals was licensed E1211 and E1210 from Eisai in 2015, and renamed APX001 and APX001A, respectively. Amplyx is now advancing the evaluation of APX001 in Phase 1 program using both IV and oral formulations to address the need for hospital administration, as well as continued dosage after hospital discharge. Amplyx plans to initiate Phase 2 studies in 2017.

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26G-ISMS38 System-wide Temporal Characterization of the Phosphoproteome of Non-small-cell Lung Cancer Cells Treated with Erlotinib

○ Adachi JUN1, Yuichi ABE1, Maiko SHIMIZU1, Marina KISHIDA1, Ayako SATO1, Takeshi TOMONAGA1

1Laboratory of Proteome Research National Institutes of Biomedical Innovation, Health and Nutrition

Phosphoproteome is one of key signatures to understand the mode of action and mechanism of drug resistance of kinase inhibitors at the molecular level, pathway level and system level. We developed sensitive and high-throughput phosphoproteome and tyrosine phosphoproteome analysis platform and performed temporal characterization of non-small-cell lung cancer cell lines treated with erlotinib.We obtained phosphoproteome and phosphotyrosine-proteome profiles of two erlotinib-sensitive cells and four erlotinib-resistant cells treated by erlotinib for 0 h, 6 h and 24 h. We quantified over 12000 phosphorylation sites by phosphoproteome analysis and over 600 phosphorylation sites on tyrosine residue by phosphotyrosine-proteome. We extracted kinases and other enzymes which are up-regulated in resistant cells and selected 46 inhibitors for drug screening. 24 of 46 inhibitors inhibited cell growth of at least one resistant cell line. Our sensitive and high-throughput phosphoproteome and tyrosine phosphoproteome analysis platform has a potential to identify pharmacoproteomic markers of drug efficacy as well as candiates of molecular targets to overcome drug resistance.

26G-ISMS37 Novel Development of Chemotherapy for Relapsed and Refractory AML Based on the Promising Functional Mechanism of Cytidine Analog, DFP-10917

○Masakazu FUKUSHIMA1, Kenzo IIZUKA1, Chung ZHANG1, Cheng JIN1, Kiyoshi ESHIMA1

1Division of Research and Development, Delta-Fly Pharma, Inc.

Acute myeloid leukemia (AML) is still progressed disease vigorously challenging to urgently improve a prognosis in patients. At present time, induction-chemotherapy with cytarabine (one of cytidine analog) combined with anthracycline drugs has been frequently conducted for the treatment of AML, and sequential consolidation-chemotherapy with almost same regimen is performed for patients. However there are few suitable treatment options for patients with relapsed and refractory AML. We developed a new generation of cytidine-type antitumor nucleoside, DFP-10917 and investigated the antitumor efficacy and functional mechanism of this drug in vitro and in vivo using human tumor cells. DFP-10917 showed the most potent antitumor activity on tumor models in mice following its prolonged (14-days) infusion at very low-dose (4.5 mg/kg/day) compared to short injection of DFP-10917 and of other cytidine analog. Under such prolonged dosing schedule, DFP-10917 is converted to its nucleotide form and subsequently incorporated into DNA in tumor cells which cause DNA-strand breaks resulting in G2/M phase-arrest by cellular checkpoint regulators and resultantly formed the ultimate apoptotic cells. In contrast, cytarabine is converted to their nucleoside-triphosphates and then inhibit DNA polymerase activity leading to protection of DNA biosynthesis during the S-phase of the cell cycle.To evaluate clinical efficacy and toxicity in phase I/II study of DFP-10917, AML patients were treated with continuous infusion (CI) of DFP-10917. In phase I study, low-dose (6 mg/m2) 14-day CI of DFP-10917 was found to result in a clinical benefit to patients as recommended dose and schedules. In phase II study, total 29 patients were enrolled and the response rate and the median survival time in relapsed/refractory AML patients were 48% and 7.3 months, respectively. No patients discontinued DFP-10917 treatment due to unacceptable drug-related toxicity. Further study of DFP-10917 in a phase III study in AML is planned.

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26G-ISMS40 Lenvatinib Mesilate (LEN) Enhanced Antitumor Activity of a PD-1 Blockade Agent by Potentiating Th1 Immune Response

○ Yu KATO1, Xingfeng BAO2, Shannon MACGRATH2, Kimiyo TABATA1, Yusaku HORI1, Sho TACHINO1, Mark MATIJEVICI2, Yasuhiro FUNAHASHI1, Junji MATSUI1

1Eisai Co., Ltd., Tsukuba, Ibaraki, Japan, 2Eisai Inc. Andover, MA, USA

Lenvatinib (LEN) selectively inhibits the kinase activities of VEGFR1-3, FGFR1-4, KIT, PDGFRα, and RET, which are involved in tumor angiogenesis and tumor cell proliferation in several cancer types. Currently, Phase 1b/2 clinical trials of the combination of LEN and pembrolizumab (a monoclonal antibody [mAb] that blocks the interaction between PD-1 and its ligands) are ongoing for selected types of cancer including renal cell carcinoma, melanoma and non-small cell lung carcinoma, etc. In this study, we will report that tumor associated macrophage and regulatory T cell population were downregulated by treatment of LEN, and combination of LEN with PD-1 mAb showed more potent antitumor activity in CT26 mice tumor syngenic model compared with either single treatment alone. Notably, complete tumor regressions were detected in some mice with combination treatment in the H22 mice tumor syngenic model. Re-inoculation of fresh H22 cells into these cured mice was rejected. BioMap analysis showed that PD-1 mAb increased both Th1 and Th2 cytokines, LEN decreased Th2 cytokines, and combination treatment increased Th1 cytokines but decreased Th2 cytokines. The results indicate that the combination of LEN with PD-1 mAb was more effective than single-agent treatment in multiple syngeneic tumor models and was accompanied with a potent antitumor immune response.

26G-ISMS39 Identification of WAC-224, a Novel Anticancer Quinolone as a Human Topoisomerase II Inhibitor

○ Tomonori YAMAGUCHI1, Kenji ITOH1, Taichi UESHIMA1, Rumiko SHIMABARA1, Yohei KAWAKUBO1, Masayuki SATO1, Junpei YAMASHITA1, Tatsuya HIRANO1, Akira YAZAKI1

1Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd.

Topoisomerese II inhibitors, such as Anthracyclines, are an important class of chemotherapeutic agents, which are employed for the treatment in multiple types of cancers including acute myeloid leukemia (AML). However, the therapeutic applications of Anthracyclines are limited because of a cumulative cardiotoxicity and an efflux-mediated drug resistance. WAC-224 is a novel anticancer quinolone derivative targeting human topoisomerase II and has the superior characteristics in potency and safety both in vitro and in vivo compared with Vosaroxin (QINPREZO®, formerly SNS-595), which showed lower potential for cardiotoxicity in the clinical trials. In our evaluations, WAC-224 had higher selectivity for cancer cells versus normal cells in its antiproliferative activity; the IC50 value was 1.4 nM for MV4-11 AML cell line versus > 50 μM for MRC-5 normal cell line. WAC-224 also showed the potent in vitro activity against multi drug-resistant cell lines such as MES-SA/Dx-5. Additionally, in vivo murine xenograft studies confirmed the potent therapeutic effects of WAC-224 for therapy of different types of cancers including multi-drug resistant one. These results suggest that WAC-224 is a potentially effective therapeutic agent for leukemia and multi-drug resistant cancers.

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26G-ISMS42 Anti-Helicobacter Pylori Activity of a Novel Derivative of Intervenolin ○ Tomokazu OHISHI1, Toru MASUDA1, Shun-ichi OHBA1, Chigusa HAYASHI2,

Hikaru ABE3, Masayuki IGARASHI2, Takumi WATANABE3 , Daniel Ken INAOKA4, Kiyoshi KITA5, Masakatsu SHIBASAKI3, Manabu KAWADA1,6

1Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, 2Institute of Microbial Chemistry (BIKAKEN), Laboratory of Microbiology, Microbial Chemistry Research Foundation, 3Institute of Microbial Chemistry (BIKAKEN), Laboratory of Synthetic Organic Chemistry, Microbial Chemistry Research Foundation, 4Center for International Collaborative Research, Nagasaki University, 5School of Tropical Medicine and Global Health, Nagasaki University, 6Institute of Microbial Chemistry (BIKAKEN), Laboratory of Oncology, Microbial Chemistry Research Foundation

Colonization and infection of Helicobacter pylori (H. pylori) is a major cause of gastric diseases including gastritis, peptic ulcers, and gastric cancer. Therefore, eradication of H. pylori leads to prevention of gastric diseases. Although standard treatment for H. pylori involves a combination of antibiotics, they kill most bacteria in our body, leading to the occurrence of side effects. We previously found that an antitumor agent intervenolin (ITV) also exhibits selective anti-H. pylori activity. Here we demonstrate that a novel derivative of ITV showed selective anti-H. pylori activity like ITV without any effect on other bacteria including intestinal bacteria. Interestingly, oral monotherapy of the ITV derivative had a stronger anti-H. pylori activity without any side effects in a mouse H. pylori-infection model than that of ITV and the standard triple therapy of a proton pump inhibitor and two antibiotics. These results suggest that the ITV-derivative would be a new potential therapeutic agent for H. pylori infection treatment. Now, we are trying to identify a molecular target of the ITV-derivative against H. pylori.

26G-ISMS41 Identification of Blood-based Gene Expression Biomarkers for Major Depressive and Bipolar Disorders

○ Seiji NAKAMURA1, Hiroaki HORI2, Yohei ISHIZAWA1, Kenichi MATSUBARA1, Ryo MATOBA1, Hiroshi KUNUGI2

1DNA Chip Research Inc., 2Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry

Major depressive and bipolar disorders are typical psychiatric problems affecting about 350 million people globally. Pathogenesis is not fully understood and laboratory tests for diagnosis and prognosis are not established. We have performed microarray analysis using blood samples of major depressive and bipolar disorder (n=25) patients against age, gender-matched healthy controls (n=25). Genes related to ribosomes were found to be up-regulated in patients of major depressive and bipolar disorders. Ribosomal proteins RPL17 and RPL34 were further validated by qRT-PCR using independent test cohorts (15 patients each for depressive and bipolar against healthy controls). Reproducibility of the result indicates that ribosomes related genes could serve as useful screening biomarkers.

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26G-ISMS44 Regulatory Science for R&D Promotion of Innovative Pharmaceuticals* Kazuhiko MORI1, Takao YAMORI2, ○ Toru KAWANISHI3, Takao INOUE4

1Ministry of Health, Labor and Welfare (MHLW), 2Pharmaceuticals and Medical Devices Agency (PMDA), 3National Institute of Health Sciences (NIHS), 4Japan Agency Medical Research and Development (AMED)

At present the nation’s policy for research and development (R&D) promotion of innovative pharmaceuticals and improvement of environments for the R&D is formulated by Japanese government. In the policy the enhancement and promotion of Regulatory Science (RS) touching the appropriate and rapid predict, evaluate, and judgment of quality, efficacy and safety of pharmaceuticals is especially stressed. Following the nation’s policy, the MHLW is promoting the strategy package (Strategy of SAKIGAKE) facilitating all the process from R&D, clinical research/trials, pre- and post- marketing safety, insurance coverage, through globalization of innovative products which are to be put into practical use, targeting innovative pharmaceuticals which can cure serious illnesses. In concert with the MHLW, the PMDA is building up the systems, such as priority consultations, prior assessment, and priority reviews. The PMDA is taking various approaches such as the introduction of data mining methods and safety evaluation of drugs based on pharmaco-epidemiological methods utilizing electronic medical records, or construction of medical information database (MID-NET), to enhance and advance safety measures. The PMDA has also established the Science Board consisting of external experts to discuss the evaluation methods of innovative drugs. The pharmaceuticals-related divisions in the NIHS have carried out RS research to develop the point-to-consider documents or standardized methods for evaluating mainly quality and non-clinical safety of innovative products such as nanomedicines, fully engineered protein drugs, oligonucleotide drugs, and so on. The AMED is supporting about 80 research projects by the Grant Program naming “Research on Regulatory Science of Pharmaceuticals and Medical Devices”. *The poster is presented by Division of Regulatory Science, Pharmaceutical Society of Japan.

26G-ISMS43 Discovery of Novel 5,6,7,8-tetrahydro[1,2,4]Triazolo[4,3-a]Pyridine Derivatives asγ-secretase Modulators

○ Takafumi TAKAI1, Tatsuki KOIKE1, Minoru NAKAMURA1, Yasutaka HOASHI1, Yoshihide TOMATA1, Sachie MORIMOTO1, Yuichi KAJITA1, Toshiro YAMASHITA1, Naohiro TAYA1, Tetsuya TSUKAMOTO1, Tomomichi WATANABE1, Koji MURAKAMI1, Tomoko IGARI1, Makoto KAMATA1


γ-Secretase modulators (GSMs), which lower pathogenic amyloid beta (Aβ) without affecting the production of total Aβ or Notch signal, have emerged as a potential therapeutic agent for Alzheimer’s disease (AD). A novel series of 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a ]pyridine derivatives was discovered and characterized as GSMs. The optimization study using ligand-lipophilicity efficiency (LLE) as a drug-likeness guideline led to identification of various types of high-LLE GSMs with potent in vivo Aβ42-lowering effects by single administration. Furthermore, multiple oral administration of the representative compound significantly reduced soluble and insoluble brain Aβ42, and ameliorated cognitive deficit in novel object recognition test (NORT) using Tg2576 mice as an AD model.

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