the importance of synthetic drugs for type 2 diabetes drug discovery - expert opin. drug discov....
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1. Introduction
2. Pathophysiology of T2DM
3. Overview of current synthetic
drugs in the treatment of
T2DM
4. New synthetic compounds as
DPP-4 inh ibi tors
5. New synthetic compounds as
SGLT2 inhibitors
7. Conclusion
8. Expert opinion
Review
The importance of synthet ic drugs
for t ype 2 diabetes drug discoveryMaliheh Safavi, AlirezaForoumadi & Mohammad Abdollahi††T ehran University of Medical Sciences, Faculty of Pharmacy and Pharmaceuti cal Sciences
Research Center, T ehran, I ran
Introduction: Type 2 diabetes mellitus (T2DM) is a major metabolic,
multi-causal and heterogeneous disorder which causes significant morbid-
ity and mo rtality wit h considerable burden to healthcare resources. The
number of deaths due t o T2DM highlights the insufficiency of the cur-
rently available drugs for controlling the disease and its complications
and more needs to be done.
Areas covered: This paper reviews the updated pathobiology of T2DM that
shoul d be t argeted in drug discovery. Furt her, the arti cle provides discussion
on t he mechanism of action, side eff ects and stru ctu re of t he current ly avail-
able synthetic drugs. The aut hors specif ically evaluate tw o newer classes of
anti-di abetic agent s: di pepti dyl pept idase IV (DPP-4) and sodiu m-glucose
transpor ter-2 (SGLT2). They also present in formation on new er synthet ic com-pounds. The article also highlig hts the key int eraction s betw een synthetic
compounds and DPP-4 acti ve site residues for ratio nal drug design.
Expert opin ion : Numerous ant i-hyperglycaemic drugs are currently available
but many are limited b y their adverse effects. The identi fication of the 3D
stru ctu re of DPP-4 has opened n ew avenues fo r design, t hus aiming t o p ro-
duce drugs that directly exploit the structural characteristics of this binding
site. Further, structural- and ligand-based screening techniques have been
developed fo r designi ng novel DPP-4 and SGLT2 i nhib ito rs. There has also
been progress wi th t he design and development of novel T2DM therapeut ics
includin g: PPARa/ dual agon ists, Sir tu in 1 activators, glycogen p hosphorylase
inhibit ors and prot ein tyrosine phosphatase 1B inhibi tors. Finding new tar-
gets and synth esis methods is sti ll essential but it is becoming accepted that
no diabeti c th erapy is ‘best suit ed’ wit h each patient respond ing dif ferent ly.
Keywords: antidiabeti ca!ents, di"e"tidyl "e"tidase I # inhibitors, sodium!lucosetrans"orter
$ i nhibitors, syntheticdru!s, ty"e$ diabetes
%"ert '"in( )ru!)iscov( *$+-. 8*./--0-1-
1. Introduction
)iabetes com"rises a !rou" of metaboli c disorders characterised by chronichy"er!lycaemia2ith disorders in themetabolism of carbohydrate, fat and "roteinthat result in defects in secretion and action of insulin 34( )ysfunction andfailureof various or!ans, es"ecially theeyes, 5i dneys, nerves, heart andthebloodvessels aretheusual com"licati ons of diabetes 3$,-4( )iabetes is mainly divided into four mainty"es i ncludin! insulinde"endent diabetes mellitus *ty"e ., noni nsulinde"endent diabetes mellitus *ty"e$., !estati onal diabetes and other s"ecificty"es 3,64(
T y"e$ diabetes mellitus *T $)M. is very common andaccounts for ~ 0+--078of all diabeticcases( T he2orld2ideincreasein T $)M becomes amost im"ortanthealth concern 374( T $)M is usually accom"anied2ith insulin resistancein thes5eletal muscles and the liver, and the reduction in insuli n "roduction by the "ancreas 314( 9enetic susce"ti bility and various environmental factors 3:,;4 are alsoinvolved in T $)M( Patients 2ith T $)M are at ris5 of vascular com"lications
10.1517/17460441.2013.837883 © 2013 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X 1339All rights reserved: reproduction in whole or in part not permitted
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such as coronary artery disease, stro5e, hy"ertension,ne"hro"athy, "eri"heral vascular disease, neuro"athy and
reti no"athy 30-4( I t has been su!!ested that hi!her !lucoselevels may be a ris5 factor for dementia 364( Althou!hT $)M 2as traditionally seen in individuals over the a!eof6+, recent data from several countries confi rm that T $)Moccurs in youn!er "eo"le even in childhood 37,14( Cases ofT $)M that occurs before-+ years of a!eusually develo"diabeti cne"hro"athy, renal failure, blindness andatheroscleroticvascular diseasein their -+s 3:4(
Althou!h thereareseveral thera"euti co"ti ons availablefor the mana!ement of diabetes, most of them r es"ond only intheshorttomedium term( Further, most of current thera"iesareassociated 2ith an increased ris5 of adverseeffects such as2ei!ht !ain *sul"honylureas, thiazoli dinediones and insulin.,
hy"o!lycaemia *sul"honylureas and insulin., !astrointesti nalintolerance *metformin. and myocardial infarction *rosi!litazone. 3;,04( Researchers are tryin! to fi nd thera"ies better than thethreeoldest classes, for eam"le, insulin, sul"honylureas and bi!uanides but the ne2er ones havenot sho2n more"otency and2ereoften less effectivei n lo2erin!!lycaemia304(
Alternativeto thesesyntheti ca!ents, ne2insulin analo!ues,inhaled insuli n and many medicinal "lants arebein!investi !ated for "ossiblebenefits in diabetes 3$+-+4( Moreover, insuli n--mimeti ccom"lees havebeen synthesized in thethou!htthat these com"lees affect both diabetes and its com"lications 3-,-$4( 'f course, concerns of safety and tolerability ofcurrent treatments and the "ro!ressivenatureof T $)M callfor ne2classes of medicines( T his revie2"rovides adiscussionof current syntheti c"harmacolo!ical a!ents andne2syntheti ccom"ounds for T $)M(
2. Pathophysiology of T2DM
Unli5esim"lecharacterisation of ty"e diabetes, the"atho!enesis of T $)M is morecom"le and sti ll remains amatter of ar!ument( T hemost "roblemis that thes"ecifi caetiolo!ies
have not yet been clearly elucidated( For instance, unli5ety"e diabetes, autoimmune destruction of cells does notoccur and 5etoacidosis seldom occurs 3--4( As mentioned earlier, "eri"heral insuli n resistance and bcell dysfunction arerather involved in T $)M 3-64( Insulin resistance and therelated conse
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5inaseC( T hesearethe5ey si!nallin!molecules in theactivation of !lucoseu"ta5e, inhibition of a"o"tosis and synthesisof "roteins 360,7$764(
I t is thou!ht that i n adi"oseandretinal tissues, "hos"horylation on s"ecific serine sites *Ser-+:. on I RS reduces
the tyrosine "hos"horylation of the insulin rece"tor 36;,774(T hecyto5ineT Fa "lays ama@or rolethrou!h "hos"horylation of theIRS "rotein on Ser-+: site( T Fainducedinhibition of I RS si!nallin!can reduceA5t "hos"horylationand sto" the insuli n si!nallin! "ath2ay 3-0,6;4( Also, it hasbeen sho2n that T Fa causes mar5ed do2nre!ulati on ofthe adi"ocytes and muscle cells insulinre!ulable !lucosetrans"orter 3714(
Accordin!to recent studies, thecirculatin!I? 1 correlates2ith insulin sensiti vity in obese humans 37:4( T his meansthat both T F a and I?1 and other adi"ocytes"ecifi csi!nallin! elements such as resistin and le"tin can alter insuli nsensitivity by "rovo5in! diverse 5ey ste"s in the "rocess ofinsulin action 3-1,7;4( Any defect in i nsulin action or theIRS
tri!!ers bcells in a2ay to cause T $)M 3704( T heinter"laybet2een insulin resistance and bcell dysfunction remainshi!hly com"le 31+4( Studies of i nsulinresistant animals i llustrate an im"ortant rolefor e"ansion of thebcell mass andenhanced bcell function as the com"ensatory mechanisms 314( In most obese and insulinresistant individuals,bcell com"ensati on reduces dueto hy"er!lycaemiaand li"idtoicity 31$,1-4( Continuous declineof bcell function usually
ends u" in bcell ehaustion and finally bcell failure anddiabetes 31+4(
umerous studies have demonstrated that enhanced "roinflammatorycyto5ines, freeradicals andoidativestress arecentral events to thedevelo"ment of diabeti ccom"lications3-,16114(
)ominant causeof oidativestress in diabetes is !lucoseautoidation that leads to "roduction of free radicals 31:4( 'idativestress causes bcell death viainduction of mitochondrial stressdurin!develo"ment of diabetes( In "ancreaticb cells, im"ortanttar!ets for an oidant insult are AT Pde"endent "otassium*BAT P. channels and cell metabolism 31;4( T heefficacies of different a""roaches in thereductionof diabetesinducedoidativestress have been studied and usa!e of antioidants as thesu""lement to dru! re!imen of T $)M "atients has beenrecommended310:04( riefly, the"athobiolo!y of T $)M 2hichareconsidered as tar!ets for classicand current syntheticdru!saresummarisedin Figure1(
3. Overview of current synthetic drugs in thetreatment of T2DM
3.1 Biguanides
T heclass of bi!uanides includes themetformin andt2o2ithdra2n a!ents "henformin and buformin( T he reason for removin! "henformin and buformin from the mar5et 2asthe occurrence of fatal lactic acidosis 3;+,;4( I ntroduced inthe mar5et in 07+, metformin is a 2ellacce"ted fi rstl ine
Insulinresistance Thiazolidinedionesbiguanides
Biguanides
Sulphonylureasnon-
sulphonylureasGLP-1 analogsDPP4 inhibitors
Sulphonylureas
β celldysfunction
(decreased insulinsecretion)
Decreasedglucose
transport (muscleand adipose tissue)
Increasedhepatic glucose
production
Impairedglucose
tolerance
Obesity & lifestyle Genes
Type 2diabete
mellitus
Figure 1. Pathobiology and targets for current drugs in T2DM.
Importance of synthetic drugs for T2DM drug discovery
Expert Opin. Drug Discov. (2013) 8(11) 1341
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choicefor the treatment of T $) M dueto its !ood efficacy,lo2 "riceandlo2rateof adverseeffects es"ecially in lon!termuse3;$;74( Metformin reduces fasti n!"lasma!lucoseconcentrations by reducin! rates of he"atic !lucose"roduction throu!ha reduction in !luconeo!enesis and !lyco!enolysis 3;1;;4(Metformin also affects "eri"herally and im"roves s5eletal myocyte !lucose u"ta5e, reduces theoverall "lasmafree fatty acid*FFA. concentration and induces mild 2ei!ht loss throu!hreduction of caloricinta5e3;0,0+4(
Acti vation of adenosine mono"hos"hateacti vated "rotein5inase*AMPB. is r e o2ever, !astrointesti nalintolerance, such as nausea, abdominal "ain and diarrhoea,
ha""ens as asideeffect in about -+8 of theusers that l imitsthe com"liance of "atients to consume to" effectivedoses 306,074( Althou!h rare, fatal lactic acidosis mi!ht beobserved in someusers 301,0:4 and thus i t should not beusedin "atients 2ith liver disease 3074, renal dysfuncti on 30:4 andin those2ith asli!ht de!reeof creati nineelevation 30;4( T hestructure of bi!uanide*red hi!hli !ht in metformin structurein Table 1. is conventionally re"resented in a 2ron! tautomericform2hich 2as correctedin $++7 3004( T hey aremoderately stron!bases andform > Cl salts
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T a b l e 1 . C u r r e n t a n t i - d i a b e t i c s y n t h e t i c d r u g c l a s s e s .
D r u g c l a s s
D r u g s t r u c t u r e
M e c h a n i s m
o f a c t i o n
S i d e e f f e c t s
S t u d y
B i g u a n i d e
N
N
N H 2
C H 3
C H 3 N
H 2
N H
M e t f o r m i n
R e d u c e s h e p a t i c g l u c o s e
p r o d u c t i o n , i n c r e a s e s
p e r i p h e r a l g l u c o s e u t i l i s
a t i o n
a n d i n s u l i n s e n s i t i v i t y
G a s t r o i n t e s t i n a l c o m p l a i n t s
a n d l a c t i c a c i d o s i s
B h a r a t a m e t a l . 2 0 0 5 ,
L i p s k a e t a l . 2 0 1 1 [ 9 9 , 2 3 6 ]
S u l p h o n y l u r e a s
S
O
O
H N
NH HN
N O
O
O
G l i m e p i r i d e
S t i m u l a t e s i n s u l i n r e l e a s e
f r o m p a n c r e a s a n d r e d u c e s
p o s t - a b s o r p t i v e r a t e s o f
e n d o g e n o u s g l u c o s e
p r o d u c t i o n
V e r y r a r e a d v e r s e e f f e c t s
c o m p a r e d t o o t h e r
s u l p h o n y l u r e a s s i d e e f f e c t s
s u c h a s h y p o g l y c a e m i a a n d
w e i g h t g a i n
K o r y t k o w s k i 2 0 0 4 ,
B e c
i c e t a l . 2 0 0 3 [ 1 0 7 , 2 3 7 ]
N o n - s u l p h o n y l u r e a s
O N H
H
H O
O
N a t e g l i n i d e
I n c r e a s e s i n s u l i n s e c r e t i o n i n
t h e p a n c r e a s
M i l d g a s t r o i n t e s t i n a l
c o m p l a i n t s a n d w e i g h t g a i n
C h a c h i n e t a l . 2 0 0 3 ,
C a m p b e l l 2 0 0 5 [ 1 1 9 , 1 2 0 ]
T h i a z o l i d i n e d i o n e s
H N
O
S
N H
O O
N
R o s i g l i t a z o n e
L o w e r s i n s u l i n r e s i s t a n c
e i n
p e r i p h e r a l t i s s u e b y
a c t i v a t i n g P P A R - g
W e i g h t g a i n , f l u i d r e t e n t i o n
a n d h e a r t f a i l u r e
Y k i - J a r v i n e n 2 0 0 4 ,
D e f r o n z o 2 0 0 9 [ 1 2 5 , 1 2 8 ]
D i s a c c h a r i d a s e i n h i b i t o r s
O O H O H
O
H
O
O O H
O H
O
H O
H O
O O H
H O
N H
H O
O H
H O
H O
H 3 C
A c a r b o s e
I n h i b i t s i n t e s t i n a l a -
g l u c o s i d a s e e n z y m e s
G a s t r o i n t e s t i n a l d i s t u r b a n c e
s u c h a s f l a t u l e n c e ,
a b d o m i n a l d i s t e n s i o n ,
s t o m a c h r u m b l e a n d
d i a r r h o e a
B a l f o u r e t a l . 1 9 9 3 ,
C l i s s o l d a n d E d w a r d s
1 9 8 8 [ 1 4 1 , 2 3 8 ]
Importance of synthetic drugs for T2DM drug discovery
Expert Opin. Drug Discov. (2013) 8(11) 1343
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T a b l e 1 . C u r r e n t a n t i - d i a b e t i c s y n t h e t i c d r u g c l a s s e s ( c o n t i n
u e d ) .
D r u g c l a s s
D r u g s t r u c t u r e
M e c h a n i s m
o f a c t i o n
S i d e e f f e c t s
S t u d y
G L P 1 a g o n i s t s
T h r S e r A s p V a l S e r
G l u G l y G l n
A l a A l a
L y s
C O O H
O
N H
H
O
C H 3
G l u
P h e
I l e
A l a
T r p
L e u
V a l
A r g
G l y
A r g
G l y
S e r
L e u
T y r
P h e
T h r
G l y
G l u
A l a
H i s
L i r a g l u t i d e
S t i m u l a t e s i n s u l i n
b i o s y n t h e s i s a n d s e c r e t i o n ,
i n h i b i t s g l u c a g o n s e c r e t i o n
a n d s l o w s g a s t r i c e m p t y i n g
N a u s e a a n d v o m i t i n g
W a
j c b e r g a n d A m a r a h
2 0 1 0 , M a d s b a d
2 0 0 9 [ 1 5 9 , 2 3 9 ]
D P P - 4 i n h i b i t o r s
H N
O
N
O H
N
V i l d a g l i p t i n
I n h i b i t s D P P - 4 t h a t i m p r o v e s
g l y c a e m i c c o n t r o l
F e w g a s t r o i n t e s t i n a l
d i s t u r b a n c e
G u p t a e t a l . 2 0 0 9 ,
P a n
i n a 2 0 0 7 [ 1 6 8 , 2 4 0 ]
S G L 2 i n h i b i t o r s
O
O H
O H
O H
H O
C H 3
S
F
I n v o k a n a ( c a n a g l i f l o z i n )
I n h i b i t s S G L T 2 i n t h e k i d n e y s
L o w i n c i d e n c e o f
h y p o g l y c a e m i a a n d g e n i t a l
i n f e c t i o n s i n f e m a l e s
N o m u r a e t a l . 2 0 1 0 ,
R o s e n s t o c k e t a l .
2 0 1 2 [ 1 7 9 , 2 4 1 ]
D o p a m i n e - 2 a g o n i s t s
H N
N
B r
H H N
O
N
O O
N
H O
O
H
C H 3 S O 3 H
B r o m o c r i p t i n e
R e s e t s a b n o r m a l l y e l e v a
t e d
h y p o t h a l a m i c d r i v e f o r
i n c r e a s e d p l a s m a g l u c o s e ,
t r i g l y c e r i d e a n d F F A l e v
e l s
F a t i g u e , n a u s e a , v o m i t i n g ,
d i z z i n e s s a n d h e a d a c h e
K e c h e 2 0 1 0 ,
K u m a r e t a l .
2 0 1 2 [ 1 8 1 , 1 8 2 ]
M. Safavi et al.
1344 Expert Opin. Drug Discov. (2013) 8(11)
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3.4 Thiazolidinediones
T ro!litazone 2as the fi rst thiazolidinedione a""roved as a!lucoselo2eri n! thera"y for "atients 2ith T $)M in00: 30;,$4( T r o!litazone2as subse
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features andlar!er bindin!"oc5et of this rece"tor "rovidene2insi!hts into the molecular details of "e"tide li!and bindin!andamorereliablestr uctural tem"latefor thedesi!n of s"ecificand "otent small molecules for thetreatment of T $)M 37-4(
T heshort halflife*tE$ ~ --(7 min. of 9?P, becauseof their ra"id inactivation by di"e"tidyl "e"tidase I#*)PP6. in the circulation, is a ma@or difficulty for itsuse 360,764( %enatide is asynthetic form of eendin6 thatoccurs naturally in thesalivaof the9ilamonster *alar!evenomous lizard nativeto south2estern United States. and i tsamino acid se o2ever, at this time, the tolerance and safety "rofi le of)PP6 inhibitors are considered as ecellent( Possibleincreased ris5 of acute "ancreatitis in the short term andoccurrence of chronic "ancreatiti s in the lon!er term areamon! concerns attr ibuted to increase in 9?P levels(onconsistent results re!ardin! a "ossible effect of 9?Pand)PP6 inhibitors on theeocrine"ancreas 2erere"orted
in various animal models 3104( In vie2 of li 5ely toic sideeffects associated 2ith the inhibition of other members of)PP family *inhibition of 2hich 2as lin5edtotoicity in animal studies., it seems necessary to desi!n selecti veinhibitorstar!etin! )PP6 over )PP; and )PP0 3:+4( Achievin!desired selectivity to2ard theinhibition of )PP6 over other related "e"tidases such as )PP; and )PP0 and lon!acti n!"otential for maimal efficacy arethemain challen!es(
3.8 Sodium-glucose t ransport er-2 inhibitors
Cana!liflozin from the ne2 class of medications calledsodium!lucose trans"orter$ *S9?T $. inhibitors 2asa""roved by F )A in March $+- 3:4( Althou!h there are
several candidates, S9?T $ inhibitors such as da"a!lifl ozinand I+::- are no2 in various sta!es of clinical develo"ment, and the"hlorizine, ser!lifl ozin and remo!liflozin havebeen discarded 3:$4(
Bidney "lays a 5ey role in !lucosehomeostasis, "rimarilyby the r eabsor"tion of fi ltered !lucose es"ecially by theS9?T $ located in the"roimal convoluted tubule( S9?T ,theother S9?T s isoform, is the5ey trans"orter for !lucoseabsor"tion in the!astrointestinal tract and"lays only aminor role in the 5idney 3:-,:64( T he e"ression of S9?T $ andother renal !lucose trans"orters 2ere elevated in diabetic"atients 3:74( S9?T $ inhibitors, 2ith a!reater selectivity for S9? T $ versus S9? T , offer a considerable advanta!e as"otential antidiabeti c medications, because of their ability
to inhibit renal !lucosereabsor"tion and subse
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structure*!lucosiderin!i s hi!hli !hted in red in cana!liflozinstructurein theTable1.( Since, the'lin5a!eof thestructureof S9?T $ inhibitors is a metabolic tar!et for b!lucosidaseenzymes that can restrict the activity of S9?T $ inhibitorsin vivo, ne2er candidate 2ith aC!lucoside lin5a!e such ascana!liflozin have been synthesized 3:;4( Cana!lifl ozin as aC!lucoside bearin! a heteroaromati c rin! has im"rovedmetabolicstability in com"arison to '!lucoside3:04(
3.9 Bile acid sequestrants/dopamine-2 agonists
From this cate!ory, t2o classes of dru!s 2ere alreadya""roved for other diseases( Colesevelam hydrochloride is abile acid se
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NH2
N
O
HO
C
Saxagliptin [244,245]DPP-4 IC50: 26 nMDPP8/DPP4 > 400 foldDPP9/DPP4 > 75 fold
N
F
F
F
NH2 O
NN
N
CF3
Sitagliptin [243]DPP-4 IC50: 18 nMQPP IC50 > 100 μMDPP8 IC50: 48 μM
HN
O
N
OH
CN
Vildagliptin [246]DPP-4 IC50: 3.5 nMQPP IC50 > 500 μM
N
C
NH3+
TFA-N
CH3
O
CH3F
O
NO
CH3 CH3
1 [189]DPP-4 IC50: 0.025 μMQPP IC50 > 100 μMDPP-9 IC50 > 100 μMDPP-8 IC50 > 100 μM
NH3C
CH3
O N
CH3
NH3+
Cl-
O
F
2 [189]DPP-4 IC50: 0.016 μMDPP-8 IC50: 25 μMDPP-9 IC50 > 100 μM
F
F
F
N
NH2 O
N
N
CF3
CH3
H
F
3 [190]DPP-4 IC50: 0.0058 μMQPP IC50: 15 μMDPP-8 IC50: 46 μMDPP-9 IC50 > 100 μM
NCN
OHN
N
H
H
O
N
CH3
CH3
4 [191]DPP-4 IC50: 0.009 μMDPP-8 IC50: 17.38 μMDPP-9 IC50: 5.7 μM
N
CNHN
NH
O
CH3 CH3
O
N
N
N
CH3
HCl
5 [193]DPP-4 IC50: 3.8 nMDPP-8 IC50: 68 nMDPP-9 IC50: 60 nM
N
N
NH O
N
S
N
CF3
6 [194]DPP-4 IC50: 0.37 nMDPP-8 IC50: 72.4 nMDPP-9 IC50: 105 nM
N
S
ONH
N
N
N
N
CH3
7 [197]DPP-4 IC50: 0.37 nMDPP-8 IC50: 260 nMDPP-9 IC50: 540 nM
FF
F NH
NH2 O
N
NN
N
CF3
8 [163]
DPP-4 IC50: 0.031 μMDPP-8 IC50: 78.5 μMDPP-9 IC50: 41.6 μM
Figure 2. Schemati c representat ion of chemical structure of some examples of the pepti domimetic DPP-4.
M. Safavi et al.
1348 Expert Opin. Drug Discov. (2013) 8(11)
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"e"tidases, )PP; and )PP0 30:4( T he 5ey interactions of
thevil da!li"tin and saa!li"tin structures 2ith )PP6 activesiteresidues are"resented in Table2(
oshidaet al( desi!ned novel "yrroli dinederivati ves 2ithout electro"hilicnitrilemoiety focused on the substituent atthe g"ositi on of "roline moiety of "rolylthiazolidine corestructure to2ards increasin! theaffi nity to theS$ subsiteof)PP6 306,0;,004( Accordin!to"revious re"orts, introducin!an electrondefi cient 6aryl"i"erazineresults in hi!hly "otent
and lon!lastin! inhibitors 3$++4( Fused bicyclic heteroaryl"i
"erazinesubsti tuted at theg"osition of the"rolinestructurein theinvesti!ation of ? "rolylthiazoli dines lac5i n!theelectro"hil ic nitrile 2as "reviously e"lored( Com"ound *6.*$trifluoro 100 μMDPP-9 IC50 > 100 μM
N
NN
N
O
O
CH3
N
N
N
NH2CH3
Linagliptin [247]DPP-4 IC50: 1 nMQPP IC50 > 100 μMDPP-8 IC50: 40 μMDPP-9 IC50 > 10 μM
F
F
F N
NH3+TFA-
NN
N O
9 [201]DPP-4 IC50: 1.2 nMQPP IC50: > 100 μMDPP-8 IC50 > 100 μMDPP-9 IC50 > 19 μM
N
N N
N
O
H
N
NH2
NN
10 [203]DPP-4 IC50: 0.001 μMDPP-4 inhib. in rat: 80%Muscarinicreceptor M1 IC50: 1.190 μM
N
NN
NH2
Cl
Cl
11 [204]DPP-4 Ki: 0.006 μmDPP-8 Ki: > 30 μMDPP-9 Ki: > 30 μM
NH2
H
N
F
F
O
N
CH3
CH3
CH3
O2S
12 [206]DPP-4 IC50: 0.055 μMQPP IC50: 63 μMDPP-8 IC50 > 100 μM
DPP-9 IC50 > 100 μM
F
F NH
NH2
N
CO2NH2
13 [206]DPP-4 IC50: 0.018 μM
QPP IC50: 22 μMDPP-8 IC50: 18 μMDPP-9 IC50: 27 μM
CH3
N
NNH2
H3C CH3
HNO
O
14 [207]DPP-4 IC50: 1.3 nM
QPPIC50: 20 μMDPP-8 IC50 > 60 μMDPP-9 IC50 > 60 μM
N
O
N
N
N
NH2C
Cl
F
O
OH
CH3
15 [208]DPP-4 IC50: 0.48 nM
QPP IC50 > 10 μMDPP-8 IC50 > 100 μMDPP-9 IC50 > 100 μM
Figure 3. Schematic representati on o f chemical structure of some examples of t he non -peptidomimet ic DPP-4 inhibi to rs.
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Table 2. Key interactions betw een inhi bit or structures and DPP-4 acti ve site residues.
DPP-4 i nh ibi tor In vol ved inh ib it or st ru ct ure Int eract io n t yp e DPP-4 resi du e St udy
Linagliptin Amino group on the piperidine Hydrogen bonding interactions Glu205, Glu206and Tyr662
Eckhardt et al.2007 [202]
C-6 carbonyl of the xanthine Hydrogen bonding interactions Tyr631Quinazoline group Stacking int eract ions Trp629Uracil group Stacking interactions Tyr547
Saxagliptin Amino group (primary) Hydrogen bonding interactions Glu205, Glu206and Tyr662
Metzler et al.2008 [242]
Carbonyl group Hydrogen bonding interact ions Asn710Hydroxyl group on theadamantyl moiety
Hydrogen bonding interactions Tyr 547
Imidate nitrogen Hydrogen bonding interactions Tyr 5474,5-Methanopyrrolidine ring van der Waals interactions Val711, Val656, Tyr662,
Tyr666, Trp659and Tyr547
Nitrile of the cyanopyrrolidine Covalent bond Ser630Sitaglipt in b-Amino group Hydrogen bonding interact ions Glu205, Glu206
and Tyr662Zhu et al. 2013,Kim et al.2005 [163,243]Carbonyl group Hydrogen bonding interact ions Tyr547
Triazolopiperazine Stacking int eract ions Phe357Trifluoromethyl group on
the triazolopiperazine
Ionic Bonds Arg358 and Ser209
Trifluorobenzyl group Hydrophobic interactions Ser630, His740, Trp659,Tyr631, Tyr662and Tyr666
Vildagliptin Amino group Salt bridge interactions Glu205, Glu206 Nabeno et al.2013 [195]Carbonyl group Hydrogen bonding interact ions Asn710
Hydroxyl group on theadamantyl moiety
Hydrogen bonding interactions His126 and Ser209
Imidate nitrogen Hydrogen bonding interactions Tyr547Nitrile of the cyanopyrrolidine Covalent bond Ser630
6 Amino group of t he proline Salt bridge int eract ions Glu205 and Glu206 Yoshida et al.2012 [194]Carbonyl group Hydrogen bonding interact ions Asn710
Quinolyl ring Stacking interactions Phe357CH--p interaction Arg358
Trifluoromethyl on thequinolyl ring
Imperfect interact ion Tyr585
7 (teneligliptin) Amino group of the proline Salt bridge interactions Glu205 and Glu206 Yoshida et al.2012 [197]Carbonyl group Hydrogen bonding interact ions Asn710
Phenyl on the pyrazolyl ring Hydrogen bonding interactions Ser209 and Arg358Hydrogen bonding interactions Val207
Piperazinyl ring CH--p interaction Phe357Pyrazolyl ring Hydrophobic int eract ions Phe357
8 Amino group Salt bridge interactions Glu205 and Glu206 Zhu et al.2013 [163]Trifluoromethyl group on
the triazolopiperazine-Interactions Tyr585 and Arg356
14 Amino group on thequinoline ring
Hydrogen bonding interactions Glu205, Glu206and Tyr662
Maezaki et al.2011 [207]
2-Isobut yl group Hydrophobic int eract ion Phe3572-Oxo group on thepiperazin-2,5-dione
Hydrogen bonding interactions Lys554
5-Oxo group on thepiperazin-2,5-dione
Hydrogen bonding interactions Tyr631
Piperazin-2,5-dione ring Hydrophobic interaction Tyr54715 Amino group at the piperidine
moiety (primary)Salt bridge interactions Glu205 and Glu206 Ikuma et al.
2012 [208]Carbonyl group on thequinoline ring
Hydrogen bonding interactions Tyr631
Carboxyl group on thebenzene ring
Salt bridge interaction Lys554
3H-imidazo[4,5-c]quinolin-4(5H)-one moiety
Stacking interact ions Tyr547
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of "revious study revealed that the nonlinear *? sha"ed.structure2as moresuitablethan thelinear *I sha"ed. onein)PP6 inhibitory activity( Moreover, theJray crystal structuredetermination of com"ound*6. in com"le 2ith human)PP6 indicated that interaction bet2een the ence, the introducti on of another nonl inear structure, a lin5ed bicyclic heteroaryl !rou" onthe"i"erazineor "i"eridinemoiety, insteadof afusedbicyclicheteroaryl !rou", 2as addressed in thelatter study 2hich ledto discovery of -3*$S,6S.636*-methyl"henyl> "yrazol7yl."i"erazinyl4"yrrolidin$ylcarbonyl4thiazolidine*7., as hi !hly "otent, selecti ve, lon!l asti n! and orally active)PP6 inhibitor( T heJray cocrystal structureof com"ound*7. in )PP6 demonstratedthat thecharacteristicfiveri n!s ofcom"ound *7. fi t i nto theactive site of ) PP6 and the5eyinteraction bet2een the "henyl substi tuent on the "yrazolylri n!and theS$ etensivesubsiteof )PP6 not only raised"otency, but also increased selecti vity *Table 2.( Com"ound*7. si!nifi cantly inhibitedthei ncreaseof "lasma!lucosel evels
after an oral !lucoseloadin K uc5er fatty rats( Com"ound*7.*teneli!li"ti n. has been a""rovedfor thetreatment of T $)Min a"an on une$+$ 30:4(
T he crystal structures of )PP6 in com"le 2ith boundsita!li"tin and alo!li"tin have sho2n that a sub"oc5etformed by the catalytic residue Ser1-+ and nearby residuesis usually occu"ied by ahydro"hobicrin!!rou" such as thetrifluorobenzyl !rou"of sita!li"tin or thebenzonitrileof alo!li"tin( T 2o acidicresidues --9lu$+7 and9lu$+1 --in theS$subsite of )PP6 forms interactions 2ith amine !rou" ofsita!li"tin *Table 2.( T hese interactions bet2een sita!li"ti nand)PP6 !ivealar!eunoccu"ieds"acearoundther i!ht terminal "ortion *the fused heterocyclic rin!. 2hich could be
modified to !enerateane2 seri es of )PP6 inhibitors( Liththis rationale, 2ellestablished clic5 chemistry 2as used to
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derivedfrom)PP6 structures cocrystallised2ith small molecules ori!inatin!fromdifferent chemical classes is no2avitalinvesti !ati on in medicinal chemistry(
ased on the Jray cocrystal structure of some com"ounds, thehydro!en bondin!interaction 2ith ?ys776 maybea""licablei n thenovel desi!n of )PP6 inhibitors( > ence,Maeza5i et al( develo"ed anovel series of noncovalent ence, aseries of C!lucosides 2ith azulenerin!s in thea!lyconemoiety 2as synthesized SAR of azulenederived C!lucosideandtheinhibitory activiti es to2ards hS9? T and hS9?T $ 2eree"lored( Incor"oration of a"henolic hydroyl !rou" at thecentral benzene rin! afforded a more "otent and selecti veS9?T $ inhibitor *18., 2hich eerted astron!and sustainedantihy"er!lycaemic effect in rodent diabetic models(A monocholinesalt of com"ound*18. *M76-. 2as selected
as aclinical candidatefor usein treatin!T $)M 3$;4(A ne2 class of "otent and selectiveS9? T $ inhibitors, by
modifyin!the!lyconesidechain incor"oratin!astructurallynovel dioabicyclo3-($(4octane rin! system, 2as "re"ared 3$$$4( At first, a seri es of C7s"irocyclic C!lycoside2eresynthesized 2ith relati vely !ood "otency and selectivityfor human S9?T $ but subo"ti mal "harmaco5i neti cs 3$$-4(T he medicinal chemistry strate!y by innovative chemistry
M. Safavi et al.
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that allo2ed difficult, yet very desirable, tar!ets to besynthe
sized in an analo!uefriendly fashion and thedevelo"ment ofa "harmaco5ineti csE"harmacodynamics *PBP). modelbrou!ht more ho"e( T hese efforts led to de"rioritisation oftheC7s"irocyclicC!lycosideS9?T $ i nhibitors and focusin!on thedioabicyclo3-($(4octaneclass( I t is believed thatthe brid!ed 5etal system 2ould confer ri!idity 2ith "otentially "ositi veim"act on "otency and selecti vity( Moreover,introducti on of ahydroymethylene> bond donor !rou"at
C7 *in "lace of the s"irocycle. brou!ht more antici"ation
to reducetherateof human PhaseI I metabolism andfurther im"rovement of the "otency( T hese efforts su""orted theadvancement of com"ound *19. *PF+60::$0. into clinicaldevelo"ment that is bein! evaluated for the treatment ofT $)M 3$$$4(
#yas et al( "erformedali!andbased -) 2234 fold
NN
NH
HO
(CH3)3
20 [225]SGLT2 EC50: 3.85 μM
OH
OH
HO
HO
OCH3
O
21 (pseudo-sergliflozin) [227]SGLT2 IC50: 2.45 nMSGLT1/SGLT2 > 200000 fold
O
OH
OH
HO
HO
S
N N
S
22 [228]Inhibition rate of blood glucoselevels in oGTT: 74.85%
O
OH
OH
HO
N
Cl
23 [216]SGLT2 EC50: 161 nMSGLT1/SGLT2: 1.3 fold
Figure 4. Schematic representation of chemical structures of some SGLT2 i nhibit ors tog ether w ith their experimental
inhibitory and selectivity activities.
Importance of synthetic drugs for T2DM drug discovery
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structures such as benzisothiazole, indolizineb)!luco"yranoside, thiazolylmethyl"henyl, "yri dazine, thiazole and"yrimidinylmethyl"henyl !lucoside analo!ues( Com"arati vemolecular fi eldanalysis *CoMFA. andcom"arati vemolecular similarity indices analysis *CoMSIA. 2ere used to further e"lore the structural re
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revie2( In this revie2, thestr uctures of somecom"ounds 2ithbiolo!ical "ro"erti es are also "resented( Phenylalanine andcycloheyl alanine derivati ves and imidazo"i"eridinebasedbaminoacidderivati ves 2eredesi!nedbasedon theobservati on that modifi cati on of the"henylalanine, cycloheylalanineor "i"erazinemoiety im"roved the)PP6 "otency by severalfolds( Also the -fluoro"yrrolidine analo!ues obtained byre"lacin!the"yrrolidinerin!com"ounds *1. and*2. sho2edmore acti vity com"ared to "arent com"ound 3;0,0+4( Sincebicyclo3-(-(+4octane derivative2ith "yrrolidine$carbonitrile2as "reviously re"orted to bea"otent )PP6 inhibitor 304,azobicyclo3-(-(+4octanecom"ounds 2eresynthesized( T hediscovery of ana!li"ti n 2as accordin!to studies sho2edthat "yrazolo3,7a4"yrimidine functions as a bioisostere conveyin!much metabolicstability andsafety 30-4(
A costly com"onent of dru! discovery a""roaches isstructurebasedscreenin!*doc5i n!., 2hich is adesi!n strate!yfor ne2chemical enti ti es, or o"ti misati on of leadcom"oundsidentified by other methods, usin! the -) structure of the)PP6( T he -) structure of )PP6 could be obtained by
Jray or nuclear ma!neticresonancestudies or fromhomolo!y models( T he "rotein data ban5 is a re"ository for the-) structural data of "roteins( T he crystal structures of)PP6 havebeen "reviously disclosed and the discovery ofteneli!li"tin "erformedby aidof mentionedin sil icomethods2hich com"rise com"utati onally assessed li!andbindin!interactions 2ith )PP6( on"e"tidomimetic inhibitors of)PP6 such as -amino"i"eridines 2ith bicycliclactams substituents 2ereori!inated from sita!li"tin --a"e"tidomimetic)PP6 inhibitor, Jray crystallo!ra"hic structure alon! 2ithmolecular modellin! 3$+4( Also noncovalent
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and in vivo( aunyn Schmiedeber!s
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