DRUG DISCOVERY OVERVIEWBY

DR ANTHONY MELVIN CRASTOWorlddrugtracker

http://newdrugapprovals.wordpress.com/

http://newdrugapprovals.wordpress.com/ http://www.allfordrugs.com/ http://worlddrugtracker.blogspot.in/ http://drug-scaleup-and-manufacturing.webnode.com/ http://amcrasto.wordpress.com/

is the link to my blogs which tracks drugs worldwide

US, CANADA, JAPAN, EU, CHINA , INDIA ETC

LINK

Dedicated to my son Lionel Crasto,

He was only in first standard in school (Dec 2007) when I was Paralysed head to

toe.

His smiling face sees me through day in and day out.

Vast readership from academia and industry motivates me, and keeps me going.

Helping millions with free advertisement free websites and has million hits on google

Thanks for helping me to keep lionel smiling

Shore Your own will power and determination will

reach you to the shore even if you are drowned in the middle of a storm

Stages in drug discovery

Drug discovery Formulation Preclinical studies Clinical trails

Any drug development process must proceed through several stages in order to produce a product that is safe, efficacious, and has

passed all regulatory requirements.

Drug development process

Target

Right moleculeCandidate

drug

Preclinical documentat

ion

Clinical documentati

on

Drug Development7 years

Drug Discovery5-7 years

Drug discoveryThe process of drug discovery involves the identification of lead and its targets, synthesis, characterization, screening, and assays for therapeutic efficacy of lead. Once a compound has shown its value in in these tests, it will begin the process of drug development prior to clinical trails.

The average time required to bring a drug to the market range from 12–15 years at an average cost of $800–1000 million

ProductsDrugsTargets & Leads

Target selection

Target to Lead

Lead to

candidate

Candidate selection to FTIH

FTIH to PoC

PoC to Commit to Phase III

Phase III

File & Launch

Lifecycle mgt

The Drug Discovery and Development process is a progression fromTargets and Leads… to Drugs...to Products

9 - 16 y

12-24m 12-24m 30-33m 8-12m 12-44m 0-30m 18-66m 10-13m

Costs ~ $1 billion per successful product

Drug Discovery and Development

Compound production

Manufacturing 0.5-2 years

Preclinical Clinical

FDA/EMEA review

Drug Discovery Drug Development Registration

Launch

PhI PhII PhIII PhIV

CD(Candidate Drug) NDA(New Drug Application)

QA and regulatory

PhI PhII PhIII

Drug DiscoveryDrug Development

RegistrationPreclinical

• GLP (Good Laboratory Practice)• GCP (Good Clinical Practice)• GMP(Good Manufacturing Practice)

NDANew Drug Application

INDInvestigational New Drug

(first time in man)

Preclinical

Intellectual Property, IP (Patents)

PhI PhII PhIII

Drug DiscoveryDrug Development

RegistrationPreclinical

Patents:•Structure class•Compound specific•Synthesis•Indication•Formulation•....

Patent time:•20 years from the filing date•Drug development 10-14 years

How to find the right molecule?

Process of drug discovery

Drug Discovery Process

chemical diversity

(compound library)

test safety&efficacyin animals and

humans

gene screen and identify lead

Lead

optimisationprotein target

DrugsTargets & Leads

Target Validation & Selection Target to Lead(compounds)

Lead to candidate

Drugs

Candidate progress to FTIH and PoC in

patients

Drug developmentTarget :Naturally existing cellular or molecular structure

involved in the disease pathology on which the drug acts

Targets

Types

Target validation :Involves demonstrating that a molecular target

is critically involved in a disease process & modulation of the target is likely to have a therapeutic effect

New •Subject of discovery which include proteins whose is discovered by function basic scientific research

Established •Have a detailed description of its functions in normal pathology involved in human

Genome Disease

Potential Drug Target

Select protein of interest Pathology

Link with disease or disease process

Selection of Biological Target

Genetics

Target SelectionApproaches to Finding

a Drug Target

Screening & design

Screening :Investigation of a great number of compounds for a particular problem or feature of them

Random Screening Non-random Cross Random involves no intellectualization & assays are done with out

structural regards Non-random also known as targeted or focused & more narrow approach. compounds having a vague resemblance to weakly active compounds uncovered in a random screened

Whether the "hits" against the chosen target will interfere with other related targets - this is the process of cross-screening

Screening to Generate Hits

Types of screens◦ Functional assay◦ Binding assay

Cell response

Compound binds to cell surface receptor - this can be measured

in a “binding assay”

This can evoke a cellularresponse - which can bemeasured in a “functionalassay”

Approaches Nature of sources Chemical sources Rational approches Molecular modelling Combnitorial chemistry Biotechnology Bioinformatics Preclinical studies Clinicaltrails

Nature of source

Plant species provide a potenial source of strating or crude

material for the drug discovery

Many cardiotonics are plant derived

Microbes are the main source of antimicrobial drugs

Streptomyces species have been a source of antibiotics.

Marine environments are potential sources for new

bioactive agents.

Arabinose neucleosides discovered from marine

invertebates

Plant derivativ

es

Marine invertebrates

Microbial

metabolites

Virtual screen ( in silico)

Ligand based◦ Knowledge of other molecules

that bind to the target◦ Build on known

pharmacophore

Structure based ◦ Knowledge of three dimensional

structure of the target (X-ray or NMR)

◦ Docking

Potency In vitro

◦ Functional cell-based assays (FLIPR) Intracellular calcium mobilization (GCRP)

In vivo Species differences!◦ Potency in vivo?

Agonist induced models ( NK1 and NK2)

◦ Effective in IBS? Disease related models

Bioavailable

Permeability Metabolism

Organic Chemistry involved in Synthesis & Purification Organic chemists synthesize new drug compounds as well as isolate

and characterize natural products, such as alkaloids. In each case, there is interest in the complex relationships between chemical structure and pharmacological action.

The pharmacological activity of a compound is an involved function of the structure, and very small changes may pro-foundly modify the pharmacological effect.

These structural modifications may involve replacing one group with another at a specific point in the molecule, shifting the same group from place to place in the parent molecule, saturating valence bonds or modifying the acidity or basicity.

Total synthesis is made possible by knowledge of chemical structures and, in many instances, is important economically in reducing the cost of the drug.1 Chromatographic techniques have been widely used for the purification of newly synthesized compounds.

Involvement of different branches of Biological Sciences in New Drug Development

The first step in product characterization is to establish the precise chemical identity of the product. It is important to determine whether the material is a compound, i.e. a single chemical entity, a mixture of closely related compounds, mixture of isomers, or merely a loose molecular complex of readily dissociable components. Such information is fundamental to a proper evaluation of the biological properties of the material. For compounds of synthetic origin, identity is usually clearly defined in the great majority of cases by the synthetic route employed. However, it is essential not only that identity be confirmed by alternative means but that the means employed should be capable of providing rapid verification whenever this may be required at any stage of the development program. Modern spectroscopic techniques, such as as1H and 13C NMR and infrared spectroscopy are sensitive tools for such purposes.

Instrumental Techniques for Product Characterization

Once a new pharmaceutical lead compound has been discovered, extensive and costly efforts usually are made to prepare a series of analogues in the hope that even better activity will be found. In an effort to improve the efficiency of analogue development, a variety of statistical methods have been introduced.

They range from the Hansch approach, in which analysis of variance is used to derive an equation expressing the quantitative relationships between functional group changes and biologic activity, to pattern recognition and factor analysis methods

Statistical approaches in Drug Discovery

Preclinical documentation

Non-clinical risk and benefit assessment for◦ estimation of an initital safe starting dose in human◦ to support the clinical program

Studies◦ Pharmacodynamics◦ Pharmacokinetics◦ Toxicology

Regulatory guidelines Quality requirements

Phase I Phase II Phase IIII Registration

Carcinogenicity studies Rat and mouse 2 years dosing Expensive Critical timeline

Phase I Phase II Phase IIII

Part 2:Selecting a Drug Candidate

Topics

Lead optimisation – addition of extra properties (ADME)

Safety testingMolecules into MedicinesTesting in Humans

Optimizing Lead Compounds is an Iterative Process

MedicinalChemistry

Biology

Lead compounds from Screening

Candidate selected for testing in man

Developability

DMPK

Hypothesise, design molecules and synthesise

Analyse/rationaliseresults

Test hypothesis

Chemical source

These include semisynthetic drugs It has organic and inorganic sources Mineral resources are one of it. New source of chemical synthesis is Combinatorial Chemistry

Combinatorial chemistry: involves the synthesis or biosynthesis

of chemical libraries (a family of compounds having a certain

base chemical structure) of molecules with in a short period of

time for the purpose of biological screening, particularly for

lead discovery or lead modification.

Methods There different types of combinatorial synthesis

combinatorial synthesis Split Synthesis: Peptide Libraries Encoding Combinatorial Libraries Nonpeptide Libraries The main differences among the various combinatorial

approaches are the solid support used, the methods for assembling the building blocks, the state (immobilized or in solution) and numbers (a fraction of the total library or individual entities)

Rational approches

Hit -Lead:Hit

confirmatio

n

• Re-testing, dose response curve,secondaary screening,chemical amnebilty,biophysical techs &hit ranking and clustering

Hit expansion

• Affinity, molecular weight and lipophilicity can be linked in single parameter such as ligand efficiency and lipophilic efficiency to assess drug likness

Lead optimization

• This optimization is accomplished through chemical modification of the hit structure, with modifications chosen by employing SAR as well as structure-based design

Technological Approach

ssss Target Identification Genetics Molecular Biology Bioinformatics

Structure Determination X-ray Crystallography NMR Spectroscopy

Computer-Aided DesignMolecular ModelingComputer Graphics

Biological AssaysHigh-Throughput ScreeningComputer-Based Screening

Synthetic Chemistry Peptidomimetics Combinatorial Chemistry Pre-clinical

Trials

Preclinical studies

Acute Studies :The goal is to determine toxic dose levels and

observe clinical indications of toxicity.

Data from acute toxic studies helps determine doses for repeated dose

studies in animals and Phase I studies in humans.

Repeated Dose Studies :These are repeated dose studies may be

referred to as sub acute, sub chronic, or chronic. The specific duration

should anticipate the length of the clinical trial that will be conducted

on the new drug. Again, two species are typically required.

Genetic Toxicity Studies :These studies assess the likelihood that the

drug compound is mutagenic or carcinogenic.

Reproductive Toxicity Studies : Segment I reproductive toxic

studies look at the effects of the drug on fertility. Segment II and III

studies detect effects on embryonic and post-natal development

Carcinogenicity Studies :Carcinogenicity studies are usually

needed only for drugs intended for chronic or recurring conditions

Toxicokinetic Studies :These are typically similar in design to

PK/ADME studies except that they use much higher dose levels.

They examine the effects of toxic doses of the drug and help

estimate the clinical margin of safety

Preclinical studies & Clinical trails

Animals to Man

Conduct initial non-clinical safety studies to assess developability and potential risks for first administration to humans

Conduct additional studies to build confidence that longer term clinical trials can be conducted safely, and the medicine can be approved for use

To complete safety evaluation and assist in dose selection for first clinical trials, Safety Assessment has to:

Genetic damage? Carcinogenicity?

Aspects of a Safety Assessment

One dose Lifetime use

Acute Responses Chronic Effects

Reproduction

Development

Clinical trails

Phase I:No blinding screening,open label & done in single centre

• 20-40 max 50 • Healthy volunteers• Sometimes patients are exposed to drug one

by one

Number of subjects

• Carried out by qualified clinical pharmacologist & trained physician

• Dose is given in cumulative manner to achieve the effective dose

Associated members

• P’kinetics,P’dynamics• Emphasis of safety and tolerability

Purpose of study

Phase II :Therapeutic exploration & dose ranging May be blind or open label (4centre’s or more)

• 100-400patients or volunteers• According to specific inclusion and exclusion

criteriaNumber of subjects

• Physicians • These are trained as investigatorsAssociated members

• To establish therapeutic efficacy of drug ,dosage regimen & ceiling effect in controlled settings

• Tolerability & p’cokinetics are studied as phase I extension

Purpose of study

Phase III :Therapeutic confirmation or comparison Done in multicentre

•Randamised double blind comparitive trails are done

•Indications are finalized & guidelines for therapeutic use are formulated

• Submission of NDA for licensing is done who if satisfied grants permission for marketing

Number of subjects

•500-3000

Associated members

•physicians

Purpose of study

•To establish value of drug in relating to existing one•ADR’S on wide scale in which P’cokinetic data may be obtained

Chemical Development (CD), in collaboration with

Pharmaceutical Development (PD), is charged with

delivering a cost effective, efficacious medicine...

Drug Substance (DS)Drug Substance (DS) Drug Product (DP)Drug Product (DP)

Molecules to Medicines

Drug Substance synthesis: Scale - up

10-100g

10-100kgLab scale

Factory scale

Consult with Regulatory Authorities

FDA:US Food and

Drug Administration

EMEA:European Medicines

Evaluation Agency

MHLW:Japan Ministry

of Health Labour

& Welfare

Agencies providehelpful insight into

study design and doses

Reduce risk of conducting long,

expensive studies that don’t lead

to approval

May change Phase III clinicalplan based on

feedback

Regulatory Authorities

Food and Drug Administration

European Medicines Agency

Ministry of Health Labour and Welfare

Therapeutic Goods Administration

Health Canada

International Conference on Harmonisation

Over 120 ‘International’ markets

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Way to success Build on knowledge – creative ideas Scilled medicinal chemists Dedicated project team Serendipity and luck - prepared mind

Chemistry

Pharmacology

Toxicology Metabolis

mPK

amcrasto@gmail.comDR ANTHONY CRASTOchemistry sites https://sites.google.com/site/anthonycrastoorganicchemistry/sites---my-own-on-the-net

DR ANTHONY MELVIN CRASTO Ph.Damcrasto@gmail.com

MOBILE-+91 9323115463GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

web linkhttp://anthonycrasto.jimdo.com/ 

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