The Importance of Synthetic Drugs For Type 2 Diabetes Drug Discovery - Expert Opin. Drug Discov. (2013) 8 (11) 1339-1363.PDF-Aforoumadi-2014-02!08!08-00

Review
The import ance of synt het ic drugs

f or t ype 2 diabet es drug discovery
Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Serials Unit - Library on 11/04/13
For personal use only.
Maliheh Safavi, AlirezaForoumadi & Mohammad Abdollahi
1.
Int roduct ion
2.
Pat hophysiology of T2DM
3.
Overview of current synt het ic

drugs in the treat ment of
T2DM
4.
New synt het ic compounds as

DPP-4 inhibitors
5.
New synt het ic compounds as

SGLT2 inhibit ors
7.
Conclusion
8.
Expert opinion
T ehran University of Medical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences

Research Center, T ehran, I ran
Int roduct ion: Type 2 diabet es mellit us (T2DM ) is a major met abolic,
mult i-causal and het erogeneous disorder w hich causes signif icant morbidit y and mortality w it h considerable burden t o healt hcare resources. The
number of deat hs due t o T2DM highlight s t he insuf ficiency of t he current ly available drugs for cont rolling t he disease and it s complications
and more needs t o be done.
Areas covered: This paper review s t he updated pat hobiology of T2DM t hat
should be t arget ed in drug discovery. Furt her, the art icle provides discussion
on t he mechanism of act ion, side ef fect s and structure of the currently available synt het ic drugs. The authors specifically evaluat e t wo new er classes of
anti-diabet ic agent s: dipept idyl pept idase IV (DPP-4) and sodium-glucose
t ransport er-2 (SGLT2). They also present inf ormat ion on new er synt het ic compounds. The art icle also highlights the key int eract ions bet w een synt hetic
compounds and DPP-4 act ive site residues f or rat ional drug design.
Expert opinion: Numerous ant i-hyperglycaemic drugs are current ly available
but many are limit ed by their adverse ef f ect s. The ident ificat ion of t he 3D
structure of DPP-4 has opened new avenues for design, t hus aiming t o produce drugs t hat direct ly exploit the st ruct ural characterist ics of t his binding
sit e. Furt her, st ruct ural- and ligand-based screening techniques have been
developed for designing novel DPP-4 and SGLT2 inhibitors. There has also
been progress w it h t he design and development of novel T2DM t herapeut ics
including: PPARa/ dual agonists, Sirtuin 1 activat ors, glycogen phosphorylase
inhibit ors and prot ein t yrosine phosphat ase 1B inhibitors. Finding new t argets and synt hesis met hods is st ill essential but it is becoming accept ed that
no diabet ic t herapy is best suit ed w ith each pat ient responding dif f erently.
Keywords: anti-diabeticagents, dipeptidyl peptidaseI V inhibitors, sodium-glucosetransporter2 inhibitors, syntheticdrugs, type2 diabetes
Expert Opin. DrugDiscov. (2013) 8(11):1339-1363
1.
Int roduction
Diabetes comprises a group of metabolic disorders characterised by chronic

hyperglycaemiawith disorders in themetabolism of carbohydrate, fat and protein
that result in defects in secretion and action of insulin [1]. Dysfunction and failure
of various organs, especially theeyes, kidneys, nerves, heart andthebloodvessels are
theusual complications of diabetes [2,3]. Diabetes is mainly divided into four main
types including insulin-dependent diabetes mellitus (type 1), non-insulin-dependent diabetes mellitus (type2), gestational diabetes and other specifictypes [1,4].
T ype2 diabetes mellitus (T 2DM) is very common andaccounts for ~ 90 --95%
of all diabeticcases. T heworldwideincreasein T 2DM becomes amost important
health concern [5]. T 2DM is usually accompaniedwith insulin resistancein theskeletal muscles and the liver, and the reduction in insulin production by the pancreas [6]. Genetic susceptibility and various environmental factors [7,8] are also
involved in T 2DM. Patients with T 2DM are at risk of vascular complications
10.1517/17460441.2013.837883 2013 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X
All rights reserved: reproduction in whole or in part not permitted
1339
M . Saf avi et al.
Art icle highlight s.

.
The incidence of T2DM continues to grow rapidly

worldwide and is associated with multiple comorbidities.
Peripheral insulin resistance and b-cell failure represent
the core pathophysiological defects in T2DM.
Currently available synthetic drug therapies include
metformin, sulphonylurea and other insulin
secretagogues, thiazolidinediones, a-glucosidase
inhibitors, GLP1 agonists, dopamine-2 agonists, bile acid
sequestrants, DPP-4 and SGLT2 inhibitors.
Two latter classes (DPP-4 and SGLT2 inhibitors) are novel
and promising drugs that target novel mechanisms.
Finding new drug targets and new faster and cheaper
synthesis methods are the main goals of T2DM
drug discovery.
This box summarises key points contained in the article.
such as coronary artery disease, stroke, hypertension,

nephropathy, peripheral vascular disease, neuropathy and
retinopathy [9-13]. I t has been suggested that higher glucose
levels may be a risk factor for dementia [14]. Although
T 2DM was traditionally seen in individuals over the age of
40, recent data from several countries confirm that T 2DM
occurs in younger people even in childhood [15,16]. Cases of
T 2DM that occurs before30 years of ageusually developdiabeticnephropathy, renal failure, blindness andatherosclerotic
vascular diseasein their 30s [17].
Although thereareseveral therapeuticoptions availablefor
the management of diabetes, most of them respond only in
theshort-to-medium term. Further, most of current therapies
areassociated with an increased risk of adverseeffects such as
weight gain (sulphonylureas, thiazolidinediones and insulin),
hypoglycaemia (sulphonylureas and insulin), gastrointestinal
intolerance (metformin) and myocardial infarction (rosiglitazone) [18,19]. Researchers are trying to find therapies better
than thethreeoldest classes, for example, insulin, sulphonylureas and biguanides but thenewer ones havenot shown more
potency andwereoften less effectivein loweringglycaemia[19].
Alternativetothesesyntheticagents, newinsulin analogues,
inhaled insulin and many medicinal plants arebeing investigated for possiblebenefits in diabetes [20-30]. Moreover, insulin--mimeticcomplexes havebeen synthesized in thethought
that these complexes affect both diabetes and its complications [31,32]. Of course, concerns of safety and tolerability of
current treatments and theprogressivenatureof T 2DM call
for newclasses of medicines. T his reviewprovides adiscussion
of current syntheticpharmacological agents andnewsynthetic
compounds for T 2DM.
2.
Pat hophysiology of T2DM
Unlikesimplecharacterisation of type1 diabetes, thepathogenesis of T 2DM is morecomplex and still remains amatter
of argument. T hemost problemis that thespecificaetiologies
1340
have not yet been clearly elucidated. For instance, unlike

type 1 diabetes, autoimmune destruction of cells does not
occur and ketoacidosis seldom occurs [33]. As mentioned earlier, peripheral insulin resistance and b-cell dysfunction are
rather involved in T 2DM [34]. Insulin resistance and the
related consequences called insulin resistance syndrome
(IRS) or the metabolic syndrome are common in T 2DM,
deemed mainly linking to patients genetic background [35].
Insulin resistance is also linked to obesity [36], dyslipidemia,
hypertension and increased cardiovascular risk [37].
H owever, risk alleles in some loci seem having aprimary
impact on insulin sensitivity. Peroxisome proliferatoractivated receptor-g (PPAR-g), glucokinase regulator and
insulin-likegrowth factor 1 havebeen provedas insulin resistance locus from T 2DM susceptibility loci [38]. Obesity and
lifestyleareindependent risk factor for T 2DM [1,39]. According to short-term studies, numerous benefits of weight loss
can be achieved in overweight or obese patients with
T 2DM. T hefindingof recent study indicated that theintensivelifestyleintervention do not reducetherateof cardiovascular morbidity andmortality in overweight or obesepatients
with T 2DM [40]. Gastricbypass induces substantial and sustained weight loss and is a highly effective treatment for
obesity-related diabetes. Laboratory datasuggest that gastric
bypass exhibits reprogramming of intestinal glucosemetabolism which renders theintestineamajor tissuefor glucosedisposal, contributingto theimprovement in glycaemiccontrol
after surgery [41].
Several studies haveindicated that obesity correlates with a
low-grade inflammation of the white adipose tissue. T his
results from activation of some pro-inflammatory signalling
pathways which end upwith insulin resistance, impaired glucose tolerance and diabetes [39,42]. Recent data indicate that
whiteadiposetissuein obesepatients is infiltrated by macrophages [43]. Several pro-inflammatory factors, such as
T NF-a and I L-6, are derived not only from adipocytes but
also from infiltrated macrophages [39]. T he role of cytokines
and insulin signalling pathways should not bemissed as this
interaction results in change of insulin action [44,45]. Normally, insulin acts through binding to and activation of its
cell-surface receptors. Such receptors are made up of two a
subunits and two b subunits, which are disulfide linked
into a2b2 heterotetrameric complex. T he actions of insulin
are initiated when the receptor is bound to the extracellular
a subunits, causing phosphorylation of intracellular tyrosine
kinase domain of the b subunits and inducing a conformational change [46-48]. Phosphorylation of the insulin
receptor can activate insulin receptor substrate complexes
(IRS-1 --IRS-4). T heactivated I RS binds to thep85 regulatory subunit of phosphatidylinositol (PI ) 3-kinasethat results
in activation of p110 catalytic subunit [47,49,50]. PI (3,4,5)
P3 which is produced by enzymaticactivity of PI 3-kinaseis
akey lipid second messenger in various metabolic effects of
insulin [51]. PI (3,4,5)P3 mediates thesignal transduction to
downstream molecules including Akt and atypical protein
Expert Opin. Drug Discov. (2013) 8(11)
Import ance of synt het ic drugs f or T2DM drug discovery
Obesity & life

style
Genes
Insulin
resistance
Impaired
glucose
tolerance
Type 2
diabete
mellitus
Thiazolidinediones
biguanides
cell
dysfunction
(decreased insulin
secretion)
Sulphonylureas
nonsulphonylureas
GLP-1 analogs
DPP4 inhibitors
Decreased
glucose
transport (muscle
and adipose tissue)
Sulphonylureas
Increased
hepatic glucose
production
Biguanides
Figure 1. Pat hobiology and t arget s f or current drugs in T2DM .
kinaseC. T hesearethekey signallingmolecules in theactivation of glucoseuptake, inhibition of apoptosis and synthesis

of proteins [49,52-54].
I t is thought that in adiposeandretinal tissues, phosphorylation on specific serine sites (Ser307) on I RS-1 reduces
the tyrosine phosphorylation of the insulin receptor [48,55].
T hecytokineT NF-a plays amajor rolethrough phosphorylation of the IRS-1 protein on Ser307 site. T NF-a-induced
inhibition of I RS-1 signallingcan reduceAkt phosphorylation
and stop the insulin signalling pathway [39,48]. Also, it has
been shown that T NF-a causes marked downregulation of
the adipocytes and muscle cells insulin-regulable glucose
transporter [56].
Accordingto recent studies, thecirculatingI L-6 correlates
with insulin sensitivity in obese humans [57]. T his means
that both T NF- a and IL-6 and other adipocyte-specificsignalling elements such as resistin and leptin can alter insulin
sensitivity by provoking diverse key steps in the process of
insulin action [36,58]. Any defect in insulin action or theI RS
triggers b-cells in away to cause T 2DM [59]. T he interplay
between insulin resistance and b-cell dysfunction remains
highly complex [60]. Studies of insulin-resistant animals illustratean important rolefor expansion of theb-cell mass and
enhanced b-cell function as the compensatory mechanisms [61]. I n most obese and insulin-resistant individuals,
b-cell compensation reduces dueto hyperglycaemiaand lipid
toxicity [62,63]. Continuous declineof b-cell function usually
ends up in b-cell exhaustion and finally b-cell failure and

diabetes [60].
Numerous studies have demonstrated that enhanced proinflammatory cytokines, freeradicals andoxidativestress arecentral events tothedevelopment of diabeticcomplications [13,64-66].
Dominant causeof oxidativestress in diabetes is glucoseautoxidation that leads to production of free radicals [67]. Oxidative
stress causes b-cell death viainduction of mitochondrial stress
duringdevelopment of diabetes. In pancreaticb cells, important
targets for an oxidant insult are AT P-dependent potassium
(K AT P) channels and cell metabolism [68]. T heefficacies of different approaches in thereduction of diabetes-inducedoxidative
stress have been studied and usage of antioxidants as the
supplement to drug regimen of T 2DM patients has been
recommended [69-79]. Briefly, thepathobiology of T 2DM which
areconsidered as targets for classicand current syntheticdrugs
aresummarised in Figure 1.
Overview of current synthet ic drugs in t he

treatment of T2DM
3.
3.1
Biguanides
T heclass of biguanides includes themetformin andtwowithdrawn agents phenformin and buformin. T he reason for
removing phenformin and buformin from the market was
the occurrence of fatal lactic acidosis [80,81]. I ntroduced in
the market in 1950, metformin is a well-accepted first-line
1341
M . Saf avi et al.
choice for the treatment of T 2DM due to its good efficacy,

low priceand low rateof adverseeffects especially in long-term
use[82-85]. Metformin reduces fastingplasmaglucoseconcentrations by reducing rates of hepatic glucose production through
a reduction in gluconeogenesis and glycogenolysis [86-88].
Metformin also affects peripherally and improves skeletal myocyte glucose uptake, reduces the overall plasma free fatty acid
(FFA) concentration and induces mild weight loss through
reduction of caloricintake[89,90].
Activation of adenosine monophosphate-activated protein
kinase(AMPK) is required for metformins inhibitory effects
on glucoseproduction by hepatocytes andacetyl-CoA carboxylase activity and its inducing effects on glucose uptake by
skeletal muscles andfatty acidoxidation. I t shouldbenoticed
that AMPK is amajor cellular regulator of lipid and glucose
metabolism [91,92]. Metformin, by improvinginsulin sensitivity, alsoimproves avariety of other factors relatedtoincreased
cardiovascular risk. I t reduces the rate of myocardial infarction and all-cause mortality [93]. H owever, gastrointestinal
intolerance, such as nausea, abdominal pain and diarrhoea,
happens as asideeffect in about 30% of theusers that limits
the compliance of patients to consume top effective
doses [94,95]. Although rare, fatal lactic acidosis might be
observed in someusers [96,97] and thus it should not beused
in patients with liver disease [95], renal dysfunction [97] and
in thosewith aslight degreeof creatinineelevation [98]. T he
structure of biguanide(red highlight in metformin structure
in Table 1) is conventionally represented in a wrong tautomericform which was correctedin 2005 [99]. T hey aremoderately strongbases andform H Cl salts quitereadily. T his aspect
is being exploited in the preparation of oral formulations of
metformin with desired properties [99,100].
3.2
Sulphonylureas
Sulphonylureas as thefast insulin secretagogues aretheoldest

available class of oral glucose-lowering agents which were
introduced in themarket in the1940s and approved for use
in 1994 for T 2DM beforemetformin [85,95,101].
T hese drugs specially stimulate insulin secretion in a
glucose-independent manner by bindingto aregulatory protein called sulphonylureas receptor on thepancreaticb-cells.
After binding to the receptors, they trigger closure to K AT P
channels, membrane depolarisation and influx of calcium
through voltage-dependent channels, which subsequently
ends up in insulin secretion [102-104]. I n addition to their
pancreatic effects, sulphonylureas can enhance insulinstimulated peripheral glucose utilisation through triggering
insulin action on adiposetissueglucosetransport andlipogenesis and skeletal muscleglycogen synthase [105,106].
T his class of oral drugs include the second-generation
agents glipizide, gliclazide, glibornuride, gliquidone, glisoxepide, glyclopyramide and glibenclamide as well as the
first-generation agents acetohexamide, chlorpropamide, tolazamideandtolbutamide[107]. T hethird-generation sulphonylurea glimepiride is as effective as second-generation
1342
sulphonylureas and appears to have several clinical advantages over conventional sulphonylureas [108]. In clinical studies, glimepiride provides more stable blood glucose control,
lowers risk of hypoglycaemiaand induces less weight gain in
comparison to other sulphonylureas [108,109]. Owingto glimepiride pancreatic tissue specificity, its use may be safer in
patients with cardiovascular disease. Cardiovascular sideeffects
of thesecompounds result from their effect on K AT P channels
present in extra-pancreatictissues of thecardiacand vascular
smooth muscle [110,111].
All sulphonylureas contain a central S-phenyl sulphonylureastructure (red highlight in the glimepiride structure in
the Table 1) [107]. T hepharmacokineticand pharmacological
differences among the available sulphonylureas are a consequence of substitutions at the para-position on the benzene
ringandtheother at anitrogen residuein theureamoiety [112].
First-generation sulphonylureas (e.g., tolbutamide, acetohexamide, tolazamideand chlorpropamide) haverelatively small,
polar, hydrophilicsubstitutions. Second-generation sulphonylureas have large, non-polar, lipophilic substitutions that
penetrate cell membranes more easily, giving them greater
potency [107,112].
3.3
N=lurea insulin secret agogues
Anti-diabetic and insulinotropic properties of the nonsulphonylureamoiety of glibenclamide, subsequently named

meglitinide, have been discovered > 30 years ago. Repaglinide, nateglinide and mitiglinide are proposed as nonsulphonylurea insulinotropic agents exhibiting structural
analogy with meglitinide [113,114]. Repaglinide and nateglinide have been approved for treatment of T 2DM and
have been released into market in 1998 and 2001, respectively [115]. Repaglinide and nateglinide have a mechanism
of action that is similar to that of sulphonylureas [104].
T hey are short-acting insulin secretagogues with high
affinity and rapid association--dissociation kinetic activity
to theK AT P at theouter membraneof b-cells. T his property
of these compounds results in restoration of early phase
insulin secretion [107,113]. T he most common adverse events
of repaglinide and nateglinide are upper respiratory tract
infection, sinusitis, constipation, arthralgia, headache and
vomiting [116].
Nateglinideis D-phenylalaninederivative(phenylalanineis
highlightedas redin theTable1) which blocks K AT P channels
in thepancreaticb-cells tostimulateinsulin release[117,118]. I n
therapeuticconcentrations, nateglinidewith nosulphonylurea
or benzamido moiety induces high selectivity for thepancreaticK AT P subtypeover thecardiovascular subtype[119]. Nateglinide sensitizes pancreatic b-cells to limited amount of
glucoseandreduces theglucoseconcentration neededtostimulateinsulin secretion [118]. I n contrast to other insulin secretagogues, nateglinide has a low propensity to cause
hypoglycaemia because of its selective, early phase insulin
secretion and transient effect [120].
Disaccharidase inhibitors
Thiazolidinediones
Non-sulphonylureas
Sulphonylureas
Biguanide
Drug class
CH3
HO
Acarbose
HO
HO
HO
N
H
HO
NH2
H3C
OH
Rosiglitazone
H
N
Nateglinide
NH
NH
Glimepiride
H
N
N
HN
H
O S O
NH2
Metformin
CH3
OH O
HO
OH
NH
OH O
HO
Drug st ruct ure
Table 1. Current ant i-diabet ic synt het ic drug classes.
OH
OH OH
Inhibits intestinal aglucosidase enzymes
Lowers insulin resistance in

peripheral tissue by
activating PPAR-g
Increases insulin secretion in

the pancreas
Stimulates insulin release

from pancreas and reduces
post-absorptive rates of
endogenous glucose
production
Reduces hepatic glucose

production, increases
peripheral glucose utilisation
and insulin sensitivity
M echanism of act ion
Gastrointestinal disturbance
such as flatulence,
abdominal distension,
stomach rumble and
diarrhoea
Weight gain, fluid retention

and heart failure
Mild gastrointestinal
complaints and weight gain
Very rare adverse effects

compared to other
sulphonylureas side effects
such as hypoglycaemia and
weight gain
Gastrointestinal complaints
and lactic acidosis
Side ef f ect s
Balfour et al. 1993,

Clissold and Edwards
1988 [141,238]
Yki-Jarvinen 2004,
Defronzo 2009 [125,128]
Chachin et al. 2003,

Campbell 2005 [119,120]
Korytkowski 2004,
Becic et al. 2003 [107,237]
Bharatam et al. 2005,

Lipska et al. 2011 [99,236]
St udy
1343
1344
Dopamine-2 agonists
SGL2 inhibitors
DPP-4 inhibitors
GLP1 agonists
Drug class
O
NH
H
O
COOH
OH
CH3
OH
OH
Br
Bromocriptine
HN
H
N
O
N
HO
Invokana (canagliflozin)
HO
OH
Vildagliptin
HN
Liraglutide
His
Ala
Glu
N
O
CH3SO3H
Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu
Phe
Phe
Thr
Gly Arg Gly Arg Val Leu Trp Ala Ile
Gly
CH3
Drug st ruct ure
Table 1. Current ant i-diabet ic synt het ic drug classes (cont inued).
Resets abnormally elevated

hypothalamic drive for
increased plasma glucose,
triglyceride and FFA levels
Inhibits SGLT2 in the kidneys
Inhibits DPP-4 that improves

glycaemic control
Stimulates insulin
biosynthesis and secretion,
inhibits glucagon secretion
and slows gastric emptying
M echanism of act ion
Fatigue, nausea, vomiting,

dizziness and headache
Low incidence of
hypoglycaemia and genital
infections in females
Few gastrointestinal
disturbance
Nausea and vomiting
Side ef f ect s
Keche 2010,
Kumar et al.
2012 [181,182]
Nomura et al. 2010,

Rosenstock et al.
2012 [179,241]
Gupta et al. 2009,

Panina 2007 [168,240]
Wajcberg and Amarah

2010, Madsbad
2009 [159,239]
St udy
M . Saf avi et al.
3.4
Thiazolidinediones
T roglitazone was the first thiazolidinedione approved as a

glucose-lowering therapy for patients with T 2DM in
1997 [98,121]. T roglitazonewas subsequently withdrawn from
use, in March 2000, becauseof causing severehepatictoxicity [122]. T wo currently available PPAR-g agonists, rosiglitazoneand pioglitazone, wereapproved in 1999. T his class of
agents also known as glitazones likethebiguanidemetformin
do not increase insulin secretion but rather increase insulin
sensitivity in muscle and adipose tissue and in the liver by
activatingPPAR-g and affectinggeneregulation in thetarget
cells [123-125].
PPAR-g is essential for normal metabolism of lipids such as
adipocytedifferentiation and proliferation as well as fatty acid
uptake and storage [126,127]. T hiazolidinediones exert their
insulin-sensitisingactions by promotinggenesis of small adipocytes andredirect fat fromnon-adiposetissues, such as liver fat,
to (subcutaneous) adiposedepots [125,128]. Although thiazolidinediones may enhanceinsulin sensitivity by keepingfat where
it belongs and sparing other tissues such as the liver, skeletal
muscle and possibly b-cells from lipotoxicity, indirect effects
may also beinvolved viaalteration of genetranscription such
as adiponectin. Adiponectin, an adipocytokine, produced
exclusively by adiposetissueincreases insulin sensitivity [129-131].
T he potential of thiazolidinediones to lower glucose production by theliver or improveglucosetransport into muscle
andadiposetissuehavebeen shown [14,132]. T hemain adverse
events associated with thethiazolidinediones class areweight
gain and fluid retention that may besevereenough to exacerbateor precipitateheart failure[133,134]. T hesedrugs alsocause
slight decrease in the haemoglobin level and haematocrit,
probably without clinical consequence [125]. Pioglitazoneand
rosiglitazone are licensed for use as the second-line therapy
to metformin and glyburide, agents that have demonstrated
efficacy in decreasing the microvascular and macrovascular
complications associated with T 2DM [14].
T hiazolidine-2,4-dionestructure(red highlight in therosiglitazonestructurein theTable1) is common toall thiazolidinediones [135]. T hiazolidinedioneringhas been investigatedas
potent polar head group which is acritical binding motif in
the active site of PPAR ligand-binding domain. H owever,
these polar head groups are prone to racemisation under
physiological conditions [136].
3.5 Disaccharidase inhibit ors (a-glucosidase
inhibit ors)
T hea-glucosidaseinhibitors acarboseandmiglitol aretwoof

these agents which werereleased in the market in 1996 [95].
I nitial investigations of voglibose as another disaccharidase
inhibitor havenot been proceeded further [137,138]. Absorption
of carbohydrates requires eventual breakdown of disaccharides
intomonosaccharides by thea-glucosidaseenzymein thebrush
border of thesmall intestine. Disaccharidaseinhibitors, such as
acarbose and miglitol, inhibit digestion of carbohydrates by
affecting the breakdown of disaccharides to monosaccharides

in the intestinal epithelium. As a consequence, delayed and
decreased absorption of thesugars happen. T hea-glucosidase
inhibitors decreaseboth postprandial blood glucose and postprandial insulin levels andin that way theseimprovesensitivity
to insulin and releasethestress on b-cells [139].
T he safety of a-glucosidase inhibitors may be a definite
helpin elderly patients with T 2DM [140]. T heefficacy of acarboseandmiglitol is limitedby theadversereactions causedby
alargeamount of non-absorbeddisaccharides in theintestinal
tract with the attendant symptoms of abdominal bloating,
diarrhoea and flatulence. T hese compounds do not induce
hypoglycaemiaor weight gain [139,141].
Accordingto somestudies, acarbosedoes not directly alter
insulin resistancebut may lower postprandial plasmainsulin
levels, fasting blood glucose, glycosylated haemoglobin,
plasmatriglycerides and/or cholesterol concentrations [141,142].
Acarboseis only minimally absorbedfrom thegut andthereby
considered as anon-absorbableinhibitor that makes this drug
with no systemicadverseeffects even after long-term administration. T he symptoms, which is due to undigested carbohydrates, occur in ~ 30 --60% of patients and tend to decrease
with timeand seem to bedose-dependent [142,143]. Acarboseis
composedof an acarviosin moiety with amaltoseat thereducing terminus. Acarviosin is asugar composed of cyclohexitol
unit linked to a 4-amino-4,6-dideoxy-D-glucopyranose unit,
which is part of the acarbose and its derivatives (highlighted
as red in theTable 1) [144].
3.6
Glucagon-like pept ide 1 agonists
In April 2005, the first glucagon-like peptide 1 (GLP-1)

agonist, exenatide, was approved for the treatment of
T 2DM [145]. In 2010, other analogueliraglutidewas approved
for useas an adjunct todiet andexercisetoimproveglycaemic
control in adults with T 2DM [146]. Several additional
GLP-1 agonists, includingexenatidelong-actingrelease[15,147]
albiglutide and taspoglutide, are under development and in
various stages of clinical trials [148].
GLP-1 is agut-derivedincretin hormone, which is secreted
by the more distally located intestinal L cells. Incretin hormones are a group of gastrointestinal hormones released in
response to nutrient ingestion, which cause an increase in
theamount of insulin released even beforeelevation of blood
glucose[149]. I ncretin hormone, GLP-1 stimulates insulin biosynthesis and secretion in responseto meal ingestion, inhibits
glucagon secretion, slows gastric emptying, reduces appetite
andpromotes theregeneration andproliferation of pancreatic
b-cells [149-151].
SinceGLP-1, gastricinhibitory polypeptide(GI P) andglucagon are all pivotal in glucose homeostasis, the G-proteincoupled receptors represent important drugtargets in T 2DM.
One novel diabetes treatment strategy is activation of GLP-1
receptors andinhibition of theglucagon signal [152]. T hestructureof thehuman glucagon class B G-protein-coupledreceptor
has been reported more recently. T he distinct structural
1345
M . Saf avi et al.
features andlarger bindingpocket of this receptor providenew

insights into the molecular details of peptide ligand binding
andamorereliablestructural templatefor thedesign of specific
and potent small molecules for thetreatment of T 2DM [153].
T heshort half-life(t1/2 ~ 1 --1.5 min) of GLP-1, because
of their rapid inactivation by dipeptidyl peptidase I V
(DPP-4) in the circulation, is a major difficulty for its
use [149,154]. Exenatide is asynthetic form of exendin-4 that
occurs naturally in thesalivaof theGilamonster (alargevenomous lizard native to southwestern United States) and its
amino acid sequence shows 53% homology to human
GLP-1 [155]. Exendin-4 and GLP-1 exhibit similar insulinotropic potencies in both in vitro and in vivo models, while
exendin-4 has abetter efficacy andalonger duration of action
than thenativeGLP-1 in rodents andhumans [156]. Exenatide
andliraglutideexhibit increasedresistancetoDPP-4 degradation and thus providepharmacological levels of GLP-1. Exenatideas short-acting GLP-1 receptor agonists (t1/2 ~ 2.4 h)
is recommendedfor twicedaily dosing[154]. Nausea, vomiting
and hypoglycaemia were the most frequently reported side
effects and wereindifferent todosewhileheadacheand nasopharyngitis wereseen moreat lower dose[147]. Liraglutide, but
not short-acting exenatide, was associated with thyroid
C-cell hyperplasiaand tumours in rodents, probably due to
continuous high-doseGLP-1 agonist exposure[157]. Rarecases
of acute pancreatitis in association with use of incretinbased classes have been reported but the most of ensuing
reports showed inconsistent results [85,158]. Liraglutide is a
long-acting GLP-1 analogue (t1/2 ~ 24 h), with 96% structural identity to human GLP-1. T headdition of aC16 fatty
acid side chain using a -glutamic acid spacer at the -amino
group of lysine-26 (fatty acid palmitateis highlighted as red
in the Table 1), which allows non-covalent binding to albumin, increases the stability through formation of heptamer
mediated by thefatty acid sidechain [159].
3.7
DPP-4 inhibit ors
DPP-4 inhibitors are promising new class of anti-diabetics

that are extremely studied [10]. I n October 2006, the first
DPP-4 inhibitor, sitagliptin, was introduced in the market.
Indeed, several other drugs such as vildagliptin, saxagliptin,
alogliptin, linagliptin and anagliptin have been approved in
certain countries for the treatment of T 2DM. Other candidates havebeen demonstrated to bein an advanced stageof
clinical trials for T 2DM [160-163].
I nhibition of DPP-4, aserine protease, enhances endogenous GLP-1 activity by decreasingtherateof GLP-1 degradation, which represents apromisingapproach to thetreatment
of T 2DM [164]. DPP-4 inhibitors increase circulating
GLP-1 and GI P levels in humans, which leads to increased
glucose-dependent secretion of insulin and decreased blood
glucose, haemoglobin A1C and glucagon levels [165,166].
DPP-4 is a766 residue N-terminal dipeptidyl exopeptidase
that specifically cleaves an aminoacidsequencehavingproline
or alanine at the N-terminal penultimate (P1) position but
1346
may also cleave substrate with non-preferred amino acids at

this position [167].
DPP-4 inhibitors include diverse structural types. Many
DPP-4 inhibitors have five-membered heterocyclic rings
such as pyrrolidine, cyanopyrrolidine, thiazolidineandcyanothiazolidineas aprolinemimeticin theP1 part. Vildagliptin
structure as a cyanopyrrolidine derivatives are presented in
the Table 1 (cyanopyrrolidinering is highlighted in red) [18].
Despite the positive results of vildagliptin in clinical trials,
oneof theissues encounteredwith theuseof 2-cyanopyrrolidinederivatives is their stability in solution dueto theparticipation of cyano group in an intramolecular cyclisation
process leadingto inactiveproducts [168].
H owever, at this time, the tolerance and safety profile of
DPP-4 inhibitors are considered as excellent. Possible
increased risk of acute pancreatitis in the short term and
occurrence of chronic pancreatitis in the longer term are
among concerns attributed to increase in GLP-1 levels.
Non-consistent results regarding a possible effect of GLP-1
and DPP-4 inhibitors on theexocrinepancreas werereported
in various animal models [169]. In view of likely toxic side
effects associated with the inhibition of other members of
DPP family (inhibition of which was linkedtotoxicity in animal studies), it seems necessary to design selectiveinhibitors
targeting DPP-4 over DPP-8 and DPP-9 [170]. Achieving
desired selectivity toward theinhibition of DPP-4 over other
related peptidases such as DPP-8 and DPP-9 and longactingpotential for maximal efficacy arethemain challenges.
3.8
Sodium-glucose t ransport er-2 inhibitors
Canagliflozin from the new class of medications called

sodium-glucose transporter-2 (SGLT 2) inhibitors was
approved by FDA in March 2013 [171]. Although there are
several candidates, SGLT 2 inhibitors such as dapagliflozin
and BI 10773 are now in various stages of clinical development, and thephlorizine, sergliflozin and remogliflozin have
been discarded [172].
Kidney plays akey role in glucose homeostasis, primarily
by the reabsorption of filtered glucose especially by the
SGLT 2 located in the proximal convoluted tubule. SGLT 1,
the other SGLT s isoform, is the key transporter for glucose
absorption in thegastrointestinal tract andplays only aminor
role in the kidney [173,174]. T he expression of SGLT 2 and
other renal glucose transporters were elevated in diabetic
patients [175]. SGLT 2 inhibitors, with agreater selectivity for
SGLT 2 versus SGLT 1, offer a considerable advantage as
potential anti-diabetic medications, because of their ability
to inhibit renal glucose reabsorption and subsequent plasma
glucose-lowering effect without inducing excessive insulin
secretion [172,176].
Canagliflozin, an oral selectiveSGLT 2 inhibitor improves
glycaemic control in T 2DM by reducing renal threshold
for glucose reabsorption and increasing the urinary glucose
excretion ending up in weight loss [177]. Various SGLT 2
inhibitors have been proposed based on the glucoside
structure(glucosideringis highlighted in red in canagliflozin

structurein theTable 1). Since, theO-linkageof thestructure
of SGLT 2 inhibitors is a metabolic target for b-glucosidase
enzymes that can restrict the activity of SGLT 2 inhibitors
in vivo, newer candidate with aC-glucoside linkage such as
canagliflozin have been synthesized [178]. Canagliflozin as a
C-glucoside bearing a heteroaromatic ring has improved
metabolicstability in comparison to O-glucoside [179].
3.9
Bile acid sequest rant s/ dopamine-2 agonist s
From this category, two classes of drugs were already

approved for other diseases. Colesevelam hydrochloride is a
bile acid sequestrant that had been originally approved for
the treatment of hypercholesterolaemia in the 2000s and
approved in January 2008 to improve glycaemic control in
T 2DM adults. T he exact mechanism influencing glucose
metabolism remains unexplained [180].
T he bromocriptine mesylate, a quick release formulation
by trade name Cycloset, as an adjunct to diet and exercise
has been approved to improve glycaemic control in adults
with T 2DM on 2009 [181]. Bromocriptinemesylateis asympatholytic D2 dopamine agonist which can reverse many of
the metabolic alterations associated with insulin resistance
and obesity viaresettingdopaminergicand sympathetictone
within thecentral nervous system [182].
Clinically, bromocriptine is used in treating Parkinsons
diseasethrough activity at dopaminereceptors andin treating
hyperprolactinaemia and acromegaly. Bromocriptine was
usedfor 30 years for other indications andbasedon its activity
in modulating central glucose and energy metabolism pathways has been approved for thetreatment of T 2DM [181,183].
Bromocriptine is a semisynthetic derivative that is derived
from a natural ergot alkaloid but bromocriptine mesylate
has been chemically designated as 2-bromoergocryptine
monomethanesulfonate (salt) [182]. More information is
presented in the Table 1.
4. New synt het ic compounds as
DPP-4 inhibitors
T heDPP-4 is responsiblefor thedegradation of theincretin

hormones GL P-1 and GI P and has therefore astrong influence on insulin secretion and glucose homeostasis [184]. In
contrast to therapy with GLP-1 analogues, becauseof limitations dueto its swift inactivation, DPP-4 inhibitors increase
effective incretin levels into amore physiological range [185].
So, in therecent years, DPP-4 inhibitors havebeen noted as
valuable agents for treatment of T 2DM. Lack of selectivity
toward several closely related proline-specificenzymes seems
apossiblecauseof toxicity [186]. In this review, thediscovery
of some synthetic compounds which may be useful in
approach tonewDPP-4 inhibitors as anewanti-diabeticclass
are presented. Structurally, two distinctive classes of DPP-4
inhibitors havebeen reported [168]. Peptidomimeticinhibitors
includesitagliptin, vildagliptin and saxagliptin (Figure 2) and
the non-peptidomimetic inhibitors include alogliptin and

linagliptin (Figure 3).
4.1
Pept idomimet ic inhibit ors
T heb-methylphenylalanine-derived amides havebeen shown

tobepotent DPP-4 inhibitors, exhibitingsuboptimal selectivity and pharmacokinetics [187,188]. A series of phenylalanine
and cyclohexylalanine derivatives also known as fluorinated
pyrrolidine amides [10] were designed and assayed for their
inhibitory potency against theDPP-4 enzymeas well as their
selectivity over the related proline-specific enzymes quiescent
cell prolinedipeptidase(QPP) (DPP-II), DPP-8 and DPP-9.
T he phenylalanine series afforded compounds such as compound (1) that werepotent and selective. Amongcyclohexylalanine derivatives, the acetamide b-methyl substitute (2) was
themost potent with better oral bioavailability [189].
T he effect of substitution on the imidazopiperidinebased b-amino acid derivatives inhibitory activity against
DPP-4, DPP-8 and DPP-9 was evaluated in another study.
Introduction of asubstituent at the4-position of theimidazopiperidineunit (3) produces compounds havingDPP-4 IC50
values < 10 nM [190].
A series of novel azobicyclo[3.3.0] octanederivatives substitutedwith pyrrolidine-2-carbonitrileweresynthesizedandevaluated against DPP-4, DPP-8 and DPP-9. Among them,
compound (4) exhibited good DPP-4 activity, high selectivity,
moderate pharmacokinetic profiles and excellent in vivo efficacy in an oral glucosetolerancetest (oGT T ) in lean mice[191].
Anagliptin is apotent and highly selectiveDPP-4 inhibitor
which has been approved in Japan for the treatment of
T 2DM in 2012 [162,192]. A series of pyrazolo[1,5-a]pyrimidines
were found to be novel DPP-4 inhibitors. Compounds were
evaluated in vitrofor inhibition of human recombinant DPP-4
and also screened for selectivity over dipeptidyl peptidase
8 and9. Structure--activity relationships (SARs) for compounds
showed N-[2-(amino)-2-methylpropyl]-2-methylpyrazolo
[1,5-a]pyrimidine-6-carboxamidehydrochloride(5) (anagliptin
hydrochloride salt) as a potent and selective DPP-4 inhibitor
with uniquepharmacological profile [193].
I t is noteworthy that many known DPP-4 inhibitors have
the P-1--P-2 fragment, wherethe P-1 sitecontains aproline
mimic [10,194]. Pyrrolidine derivatives (vildagliptin and saxagliptin) have been widely explored as DPP-4 inhibitors due
to DPP-4s specificity for substrate having an aminoterminal prolineat C-2 [10]. T heir cyanopyrrolidinemoieties
bind to the S1 sub-site and form a covalent bond between
thenitrilegroupandhydroxyl of Ser630 in thecatalytictriad.
Further, their hydroxy adamantyl groups bind to theS2 subsite[195]. Vildagliptin was chemically unstableduetointramolecular cyclisation between thenitrilegroupandtheP-2 basic
aminemoiety. Saxagliptin has an improved chemical stability
by introduction of acyclopropyl ring(cis-4,5-methanobridge)
to theprolinenitrilewhich minimises cyclisation [160,196]. T he
DPP-4 inhibitors possessing the electrophilic trap such as a
nitrile group have low selectivity against other related prolyl
1347
M . Saf avi et al.
F
F
NH2
HO
HN
NH2
OH
CF3
Saxagliptin [244,245]
DPP-4 IC50: 26 nM
DPP8/DPP4 > 400 fold
DPP9/DPP4 > 75 fold
Sitagliptin [243]
DPP-4 IC50: 18 nM
QPP IC50 > 100 M
DPP8 IC50: 48 M
CH3
O
CH3
H3 C
N
NH3
TFA-
NH3
Cl-
NH2
N
H CH
CN
N
H
N
3
CN
CH3
CF3
CH3
HCl
N
N
CH3
N
N
N
N
H
CH3
5 [193]
DPP-4 IC50: 3.8 nM
DPP-8 IC50: 68 nM
DPP-9 IC50: 60 nM
F
F
NH2
N
N
H
6 [194]
DPP-4 IC50: 0.37 nM
DPP-8 IC50: 72.4 nM
DPP-9 IC50: 105 nM
F
CH3
N
4 [191]
DPP-4 IC50: 0.009 M
DPP-8 IC50: 17.38 M
DPP-9 IC50: 5.7 M
3 [190]
DPP-4 IC50: 0.0058 M
QPP IC50: 15 M
DPP-8 IC50: 46 M
DPP-9 IC50 > 100 M
CF3
2 [189]
DPP-4 IC50: 0.016 M
DPP-8 IC50: 25 M
DPP-9 IC50 > 100 M
CH3
H
N
CH3
CH3
1 [189]
DPP-4 IC50: 0.025 M
QPP IC50 > 100 M
DPP-9 IC50 > 100 M
DPP-8 IC50 > 100 M
HN
F
N
CH3
Vildagliptin [246]
DPP-4 IC50: 3.5 nM
QPP IC50 > 500 M
CH3
N
CN
O
N
7 [197]
DPP-4 IC50: 0.37 nM
DPP-8 IC50: 260 nM
DPP-9 IC50: 540 nM
O
N
H
N
N
N
CF3
8 [163]
DPP-4 IC50: 0.031 M
DPP-8 IC50: 78.5 M
DPP-9 IC50: 41.6 M
Figure 2. Schemat ic represent at ion of chemical st ruct ure of some examples of t he pept idomimet ic DPP-4.
1348
F
O
CH3
N
N
N
N
CH3
NH3+TFA-
CN
N
N
NH2
CH3
N
N
NH2
Alogliptin [246]
DPP-4 IC50 < 10 nM
DPP-8 IC50 > 100 M
DPP-9 IC50 > 100 M
Linagliptin [247]
DPP-4 IC50: 1 nM
QPP IC50 > 100 M
DPP-8 IC50: 40 M
DPP-9 IC50 > 10 M
N
N
N
NH2
NH2
CH3
Cl
O
N
N
CH3
Cl
O2
S
N
O
CH3
NH2
10 [203]
DPP-4 IC50: 0.001 M
DPP-4 inhib. in rat: 80%
Muscarinicreceptor M1 IC50: 1.190 M
12 [206]
DPP-4 IC50: 0.055 M
QPP IC50: 63 M
DPP-8 IC50 > 100 M
DPP-9 IC50 > 100 M
11 [204]
DPP-4 K i: 0.006 m
DPP-8 K i: > 30 M
DPP-9 K i: > 30 M
H3 C
Cl
CH3
NH2
H
9 [201]
DPP-4 IC50: 1.2 nM
QPP IC50: > 100 M
DPP-8 IC50 > 100 M
DPP-9 IC50 > 19 M
O
N
HN
O
CH3
NH2
N
N
O
C
CO2NH2
CH3
NH2
OH
13 [206]
DPP-4 IC50: 0.018 M
QPP IC50: 22 M
DPP-8 IC50: 18 M
DPP-9 IC50: 27 M
14 [207]
DPP-4 IC50: 1.3 nM
QPPIC50: 20 M
DPP-8 IC50 > 60 M
DPP-9 IC50 > 60 M
15 [208]
DPP-4 IC50: 0.48 nM
QPP IC50 > 10 M
DPP-8 IC50 > 100 M
DPP-9 IC50 > 100 M
Figure 3. Schemat ic represent at ion of chemical st ruct ure of some examples of t he non-pept idomimet ic DPP-4 inhibit ors.
peptidases, DPP-8 and DPP-9 [197]. T he key interactions of

thevildagliptin and saxagliptin structures with DPP-4 active
siteresidues arepresented in Table 2.
Yoshidaet al. designed novel pyrrolidinederivatives without electrophilicnitrilemoiety focused on thesubstituent at
the g-position of proline moiety of prolylthiazolidine core
structuretowards increasing theaffinity to theS2 sub-siteof
DPP-4 [194,198,199]. Accordingtoprevious reports, introducing
an electron-deficient 4-arylpiperazineresults in highly potent
and long-lasting inhibitors [200]. Fused bicyclic heteroarylpiperazinesubstituted at theg-position of theprolinestructure

in the investigation of L-prolylthiazolidines lacking theelectrophilic nitrile was previously explored. Compound (6)
(2-trifluoroquinolyl) was the most potent, long-lasting and
selective DPP-4 inhibitor. X-ray crystal structure determination of compound (6) indicates that compound (6) made
many interactions with the active site of DPP-4 (Table 2).
T he SAR study of fused bicyclic heteroarylpiperazine parts
1349
M . Saf avi et al.
Table 2. Key int eract ions bet w een inhibit or st ruct ures and DPP-4 act ive site residues.
DPP-4 inhibit or
Involved inhibit or st ruct ure
Int eract ion t ype
Linagliptin
Amino group on the piperidine
Hydrogen bonding interactions
Saxagliptin
C-6 carbonyl of the xanthine

Quinazoline group
Uracil group
Amino group (primary)

Stacking interactions
Carbonyl group
Hydroxyl group on the
adamantyl moiety
Imidate nitrogen
4,5-Methanopyrrolidine ring

van der Waals interactions
Nitrile of the cyanopyrrolidine

b-Amino group
Covalent bond
Carbonyl group
Triazolopiperazine
Trifluoromethyl group on
the triazolopiperazine
Trifluorobenzyl group

Ionic Bonds
Amino group
Carbonyl group
Hydroxyl group on the
adamantyl moiety
Imidate nitrogen
Nitrile of the cyanopyrrolidine
Amino group of the proline
Carbonyl group
Quinolyl ring
Salt bridge interactions

Ser630, His740, Trp659,

Tyr631, Tyr662
and Tyr666
Glu205, Glu206
Asn710
His126 and Ser209

Covalent bond
CH--p interaction
Imperfect interaction
Tyr547
Ser630
Glu205 and Glu206
Asn710
Phe357
Arg358
Tyr585

CH--p interaction
Hydrophobic interactions
-Interactions
Glu205 and Glu206

Asn710
Ser209 and Arg358
Val207
Phe357
Phe357
Glu205 and Glu206
Tyr585 and Arg356

Hydrophobic interaction
Glu205, Glu206
and Tyr662
Phe357
Lys554
Tyr631
Hydrophobic interaction
Tyr547
Glu205 and Glu206
Tyr631
Salt bridge interaction
Lys554
Tyr547
Sitagliptin
Vildagliptin
7 (teneligliptin)
14
15
1350
Trifluoromethyl on the
quinolyl ring
Amino group of the proline
Carbonyl group
Phenyl on the pyrazolyl ring
Piperazinyl ring
Pyrazolyl ring
Amino group
Trifluoromethyl group on
the triazolopiperazine
Amino group on the
quinoline ring
2-Isobutyl group
2-Oxo group on the
piperazin-2,5-dione
5-Oxo group on the
piperazin-2,5-dione
Piperazin-2,5-dione ring
Amino group at the piperidine
moiety (primary)
Carbonyl group on the
quinoline ring
Carboxyl group on the
benzene ring
3H-imidazo[4,5-c]quinolin4(5H)-one moiety
Hydrophobic interactions
DPP-4 residue
Glu205, Glu206
and Tyr662
Tyr631
Trp629
Tyr547
Glu205, Glu206
and Tyr662
Asn710
Tyr 547
Tyr 547
Val711, Val656, Tyr662,
Tyr666, Trp659
and Tyr547
Ser630
Glu205, Glu206
and Tyr662
Tyr547
Phe357
Arg358 and Ser209
St udy
Eckhardt et al.
2007 [202]
Metzler et al.
2008 [242]
Zhu et al. 2013,

Kim et al.
2005 [163,243]
Nabeno et al.
2013 [195]
Yoshida et al.
2012 [194]
Yoshida et al.
2012 [197]
Zhu et al.
2013 [163]
Maezaki et al.
2011 [207]
Ikuma et al.
2012 [208]
of previous study revealed that the non-linear (L-shaped)

structurewas moresuitablethan thelinear (I -shaped) onein
DPP-4 inhibitory activity. Moreover, theX-ray crystal structuredetermination of compound(6) in complex with human
DPP-4 indicated that interaction between the quinolyl ring
and the S2 extensive sub-site plays an important role for
DPP-4 inhibition [194]. H ence, the introduction of another
non-linear structure, a linked bicyclic heteroaryl group on
thepiperazineor piperidinemoiety, insteadof afusedbicyclic
heteroaryl group, was addressed in thelatter study which led
to discovery of 3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H -pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine
(7), as highly potent, selective, long-lasting and orally active
DPP-4 inhibitor. T heX-ray co-crystal structureof compound
(7) in DPP-4 demonstratedthat thecharacteristicfiverings of
compound (7) fit into the active site of DPP-4 and the key
interaction between the phenyl substituent on the pyrazolyl
ring and the S2 extensive sub-siteof DPP-4 not only raised
potency, but also increased selectivity (Table 2). Compound
(7) significantly inhibitedtheincreaseof plasmaglucoselevels
after an oral glucoseloadin Z ucker fatty rats. Compound(7)
(teneligliptin) has been approved for thetreatment of T 2DM
in Japan on June2012 [197].
T he crystal structures of DPP-4 in complex with bound
sitagliptin and alogliptin have shown that a sub-pocket
formed by the catalytic residue Ser630 and nearby residues
is usually occupied by ahydrophobicring group such as the
trifluorobenzyl groupof sitagliptin or thebenzonitrileof alogliptin. T wo acidicresidues --Glu205 andGlu206 --in theS2
sub-site of DPP-4 forms interactions with amine group of
sitagliptin (Table 2). T hese interactions between sitagliptin
andDPP-4 givealargeunoccupiedspacearoundtheright terminal portion (the fused heterocyclic ring) which could be
modified to generateanew series of DPP-4 inhibitors. With
this rationale, well-established click chemistry was used to
quickly explorethe SAR of thelinker and theterminal portion of sitagliptin. A series of 4-(2,4,5-trifluorophenyl)
butane-1,3-diamines weredesigned and elaborated as DPP-4
inhibitors. T heresults showed that compound (8) had desirable efficacy, selectivity and pharmacokinetics properties. It
is noteworthy that crystal structures of DPP-4 in complex
with bound compound (8) revealed that the trifluoromethyl
heterocycle is rotated ~ 180 and directed towards a subpocket different from thesub-sitebound by sitagliptin, providing clues for the design of new DPP-4 inhibitors. T he
key interaction between compound (8) and DPP-4 active
sitearepresented in Table 2 [163].
4.2
Non-pept idomimet ic inhibit ors
Monocyclic, bicyclic, bicycliclactams andtriazolopyridazinessubstituted 3-aminopiperidines were synthesized and evaluated for in vitro inhibition of human DPP-4, QPP, DPP-8
and DPP-9. Bicyclic lactams series were potent (DPP-4
I C50: 1.2 --8 nM) andin general hadgood-to-excellent selectivity. Compound (9) was found to be the most potent
DPP-4 inhibitor with excellent selectivity but poor pharmacokineticproperties [201].

T he X-ray crystal structure of linagliptin complexed with
DPP-4 indicatedthemanner in which theseresidues provided
a good fit (Table 2) [202]. A class of 3,5-dihydro-imidazo
[4,5-d]pyridazin-4-ones with different substituent provided.
In addition to in vitro DPP-4 inhibitory activity, the effects
of compounds on themuscarinicreceptor M1 and inhibition
of DPP-4 in rats was tested. I t should benoticed that significant M1 receptor inhibition was acharacteristicof someearly
xanthines. Compound (10) seems to beapotential candidate
showingvery potent DPP-4 inhibitor activity in vitroas well
as in vivoand only poor affinity to M1 receptors. T helonglasting strong DPP-4 inhibition (> 70% 24 h post-administration) of compound (10) is particularly noteworthy. T herefore, further works on this series, and compound (10) in
particular, will behelpful in thedevelopment of better drugs
for T 2DM [203].
Pyrazolopyrimidines areaclass of compounds under investigation. A series of pyrazolopyrimidines with different substituents on the pyrazole ring which include alkyl, aryl,
substituted aryl and carboxylic ester groups were tested
in vitro against purified human DPP-4. Favourable
DPP-4 activity, selectivity over DPP-8 andDPP-9 andample
opportunity for further optimisation aroundthepyrazolering
were the three desirable characteristics of this class of compounds. A 5-aminomethyl imidazolopyrimidines derivative
compound (11) was themost potent against DPP-4 with no
significant DPP-8/DPP-9 inhibition. T he oGT T in ob/ob
mice by compound (11) showed dose-dependent increase in
plasmainsulin levels [204].
While substituted 4-amino cyclohexylglycineanalogues in
the a-amino acid series showed good activity against
DPP-4 [205], thesubstitutedcyclohexaneandpiperidinederivatives wereprepared and assessed for DPP-4 inhibitory activity and selectivity profiles against other proline-specific
peptidases. In the cyclohexyl with sulphonamide substituent
series, N-methyl-(2,5-dimethylisoxazol-yl)sulphonamide (12)
showed the most promising potency against DPP-4 and
excellent selectivity against the off-target enzymes but poor
pharmacokinetic. AmongtheN-substitution piperidinederivatives, 3-(5-aminocarbonylpyridyl piperidine) (13) displayed
excellent DPP-4 activity with good selectivity versus other
prolineenzymes [206].
As mentioned in Table 2, many of the reported DPP-4
inhibitors includingvildagliptin and saxagliptin makeacovalent interaction with theSer630 residuein theS1 pocket. Sitagliptin and linagliptin form non-covalent interactions with
the S1, S2 or S2 extensive sub-sites in addition to the
S1 and S2 sub-sites. It appears that excess interactions may
increase DPP-4 inhibition beyond the level yielded by the
fundamental interactions with the S1 and S2 sub-sites and
are more effective than forming a covalent bond with
Ser630 in the S1 subunit [195,207]. Design of novel noncovalent inhibitors of DPP-4 using structural information
1351
M . Saf avi et al.
derivedfromDPP-4 structures co-crystallisedwith small molecules originatingfromdifferent chemical classes is nowavital

investigation in medicinal chemistry.
Based on the X-ray co-crystal structure of some compounds, thehydrogen bondinginteraction with Lys554 may
beapplicablein thenovel design of DPP-4 inhibitors. H ence,
Maezaki et al. developed anovel series of non-covalent quinoline-basedinhibitors totarget thesidechain of Lys554. Synthesis and evaluation of designed compounds against DPP-4,
QPP, DPP-8 and DPP-9 enzyme and determination of
absorption, distribution, metabolism and excretion and pharmacokineticprofiles revealed 1-[3-(aminomethyl)-4-(4-methylphenyl)-2-(2-methylpropyl) quinolin-6-yl]piperazine-2,5-dione
compound (14) -- a potent, selective and orally active
DPP-4 inhibitor with long-lasting ex vivoactivity in dogs and
potent glucose-loweringeffects in rats. A dockingstudy of compound (14) suggested that an efficient fit into thebindingsite
and a hydrogen-bonding interaction with the side chain of
Lys554 are important in enhancing the inhibitory activity.
Also, in comparison with other members of this series, it seems
that compound(14) achievedexcellent activity by takingadvantageof thedesirablepiperazin-2,5-dionesubstituent and forming hydrophobic and two hydrogen-bonding interactions,
includingtheonewith Lys554 (Table 2) [207].
I kuma et al. found a potent DPP-4 inhibitor by highthroughput screening of laboratory chemical library and
proper optimisation based on results of published DPP-4
enzyme-inhibitor docking study. Further docking studies
werecarried out to design astrategy for optimisation of lead
compound with 3H -imidazo[4,5-c]quinolin-4(5H )-one as
skeleton. Compound (15) with 2-chloro-5-fluorobenzylsubstituent on theimidazoquinolinegroup was found as potent
and highly selective DPP-4 inhibitor [208]. T he results of
dockingstudy areshown in Table 2.
New synthet ic compounds as

SGLT2 inhibit ors
5.
Inhibition of glucose reabsorption and increasing urinary

glucose excretion lead to anegative energy balance, making
these series of compounds a unique promising therapeutic
class with potential to reduce body weight in T 2DM [172].
Only sugars in ahexoseand theD-configuration aretranslocatedby SGLT . T hehydrogen bondingbetween SGLT 2 and
hydroxy groups at C-2, C-3 and C-4 and hydrophobicinteractions with theC-6 methylenegroupof thepyranosearethe
key interactions in determiningsugar specificity [209,210]. T he
b-glucosides with largeringstructures such as aromaticaglucones and the aglucones themselves are well accommodated
at the sugar-binding site and not translocated. T hey act as
inhibitors of the transport [174,209]. Various O-, C-, N- and
S-glucosides have been synthesized with high affinity and
high specificity for SGLT 2 that arein thedifferent stages of
clinical development [209]. T heb-glucosidephlorizin, thefirst
SGLT 2 inhibitors, is a O-aryl glycoside and non-selective
1352
competitive inhibitor with two moieties to bind with SGLT :

aglucosemoiety connectedwith an oxygen atom(O-glucoside)
and a hydrophobic aglycone moiety [209,211]. T he firstgeneration SGLT 2 inhibitors with O-glycosidic bond were
discontinued due to their short half-lives in vivo resulting
from glycosidase cleavage [211,212]. Second-generation SGLT 2
inhibitors adopted other forms of glycoside linkage resistant
to glycosidaseactivity such as C-glucosidestructure [213].
5.1
C-glycoside analogues of SGLT2 inhibit ors
Many C-aryl glycoside analogues containing conjugated aryl

moiety with glucosemoiety by C--C bond instead of instable
C--O--C bond have been designed and synthesized [179,214].
Among these analogues, dapagliflozin has been used as a
lead compound as many syntheticderivatives havebeen further madeon its SAR data. A series of fluorinated analogues
of dapagliflozins were designed and synthesized by incorporation of a gem-difluoromethylene group at C-4 position.
T hein vitroinhibitory activities of theseseries against human
SGLT 2 showed that some of the analogues (compound 16)
with CF2 at C-4 are better SGLT 2 inhibitors compared
with dapagliflozin (Figure 4) [215].
T hestructural similarity of D-xyloseandD-glucoseandthe
positiveresults of O-xylosides andN-b-D-xylosides [216] ledto
thedesign of anew series of C-linked indolylxylosides. SARs
studies indicatedthat ap-cyclopropylphenyl groupin thedistal position and substituents at the 7-position of the indole
moiety were necessary for optimum inhibitory activity. T he
pharmacokinetic and animal studies demonstrated that the
most potent compound7-substitutedindolylxlyosides bearing
adistal p-cyclopropylphenyl group(17) is metabolically stable
with significant efficacy on lowering blood glucose levels of
streptozotocin-induced diabeticrats [217].
I kegai et al. investigation led to the discovery of other
C-glucoside SGLT 2 inhibitors with azulene motifs [218].
Although azuleneis not acommon motif in medicinal chemistry of anti-diabeticdrugdiscovery, asearch of theliterature
indicates that certain azulene derivatives possess significant
pharmacological and therapeutic activity [219-221]. H ence, a
series of C-glucosides with azulenerings in theaglyconemoiety was synthesized; SAR of azulene-derived C-glucosideand
theinhibitory activities towards hSGLT 1 and hSGLT 2 were
explored. Incorporation of aphenolic hydroxyl group at the
central benzene ring afforded a more potent and selective
SGLT 2 inhibitor (18), which exerted astrong and sustained
anti-hyperglycaemic effect in rodent diabetic models.
A monocholinesalt of compound(18) (YM543) was selected
as aclinical candidatefor usein treatingT 2DM [218].
A new class of potent and selective SGLT 2 inhibitors, by
modifyingtheglyconesidechain incorporatingastructurally
novel dioxabicyclo-[3.2.1]octane ring system, was prepared [222]. At first, a series of C-5-spirocyclic C-glycoside
weresynthesized with relatively good potency and selectivity
for human SGLT 2 but suboptimal pharmacokinetics [223].
T he medicinal chemistry strategy by innovative chemistry
HO
CH3
OH
OH
Cl
HO
HO
OH
OH
CH3
HO
HO
HO
O
O
HO
OH
OH
OH
OH
Phlorizin [215]
SGLT2 IC50: 46.03 nM
Dapagliflozin [214]
SGLT2 EC50: 1.1 nM
SGLT1/SGLT2: 1200 fold
Sergliflozin-A [249]
SGLT2 K i: 2.39 nM
CH3
Cl
HO
O
F
HO
F
OH
F
HO
OH
HO
OH
OH
HO
OH
OH
16 [215]
SGLT2 IC50: 0.35 nM
17 [217]
SGLT2 EC50: 47 nM
SGLT1/SGLT2: 6 fold
NH
CH3
Cl
HO
HO
18 [218]
SGLT2 IC50: 8.9 nM
HO
CH3
(CH3)3
HO
OH
HO
OH
OH
OH
19 [222]
SGLT2 IC50: 0.887 nM
SGLT1/SGLT2 > 2234 fold
HO
HO
20 [225]
SGLT2 EC50: 3.85 M
S
OH
21 (pseudo-sergliflozin) [227]
SGLT2 IC50: 2.45 nM
SGLT1/SGLT2 > 200000 fold
Cl
N N
O
OH
HO
N
OH
OH
22 [228]
Inhibition rate of blood glucose
levels in oGTT: 74.85%
23 [216]
SGLT2 EC50: 161 nM
SGLT1/SGLT2: 1.3 fold
Figure 4. Schemat ic represent at ion of chemical st ruct ures of some SGLT2 inhibit ors t oget her w it h t heir experiment al
inhibit ory and select ivit y act ivit ies.
that allowed difficult, yet very desirable, targets to besynthesized in an analogue-friendly fashion and thedevelopment of
a pharmacokinetics/pharmacodynamics (PKPD) model
brought more hope. T hese efforts led to deprioritisation of
theC-5-spirocyclicC-glycosideSGLT 2 inhibitors and focusing on thedioxabicyclo[3.2.1]octaneclass. It is believed that
the bridged ketal system would confer rigidity with potentially positive impact on potency and selectivity. Moreover,
introduction of ahydroxymethyleneH -bond donor group at
C-5 (in place of the spirocycle) brought more anticipation

to reducetherateof human PhaseI I metabolism and further
improvement of the potency. T hese efforts supported the
advancement of compound (19) (PF-04971729) into clinical
development that is being evaluated for the treatment of
T 2DM [222].
Vyas et al. performed aligand-based 3D quantitativeSARs
(QSARs) study on C-aryl glucoside SGLT 2 inhibitors
(180 analogues), which belong to various diversified
1353
M . Saf avi et al.
structures such as benzisothiazole, indolizine-b-D-glucopyranoside, thiazolylmethylphenyl, pyridazine, thiazole and

pyrimidinylmethylphenyl glucoside analogues. Comparative
molecular fieldanalysis (CoMFA) andcomparativemolecular
similarity indices analysis (CoMSI A) were used to further
explore the structural requirements of C-aryl glucoside analogues for SGLT 2 inhibition. CoMFA and CoMSIA contour
map analysis offered enough information to understand the
importance of the substituent at particular positions with
respect to steric, electrostatic, hydrophobic, hydrogen-bond
donor andacceptor properties for better activity of C-aryl glucoside SGLT 2 inhibitors. For example analysis of CoMFA and
CoMSI Acontour plots revealedtheimportanceof hydrophobic
and hydrogen-bond donor and acceptor properties [224].
5.2
SGLT2 inhibit ors w it h ot her st ruct ures
T he application of ligand-based virtual screening strategy

comprising the combination of pharmacophore model with
shape-based scoring and structure clustering analysis led to
the discovery of non-glycosideSGLT 2 inhibitors. A total of
7989 compounds matchingall thefeatures describedby pharmacophoremodel werethen subjectedtoshape-basedscoring
andstructureclusteringanalysis. T otally, 80 compounds with
high scoreand structurally diversescaffolds wereselected for
biological testing, and out of these, threecompounds showed
inhibition of SGLT 2 with EC50 < 10 M. T henon-glycoside
compound (20) with EC50 = 3.85 M was the most potent
compound [225].
Most SGLT 2 inhibitors in clinical trials aretaken fromtwo
distinct series: C-aryl glycosides (e.g., dapagliflozin) and
O-aryl glycosides (e.g., sergliflozin and remogliflozin) [223].
T he abovementioned compounds were C-glucoside derivatives but showed higher cancer risk [226]. I t is thought that
themetabolicinstability of theO-glucosideSGLT 2 inhibitors
can be solved by modifying the sugar core of sergliflozin-A.
Several small-moleculecarbohydratemimics such as pseudosergliflozin weresynthesized by aregion- and stereo-selective
allylicsubstitution reaction. T hen theSGLT 2/SGLT 1 inhibitory activities of these newly synthesized compounds were
studied. T he endocyclic oxygen atom of sergliflozin-A was
replaced by a methylene unit to render the molecule free
from glycosidase degradation. I n this way, compound (21)
was found as apotent and selectiveinhibitor of SGLT 2 that
considered alead compound for further development [227].
A series of thiadiazole-based S-glycosides weresynthesized
from D-glucose, D-galactoseandavariety of phenylaceticacids
and then evaluated in vivo with an oGT T test. Of these,
5-benzyl-1,3,4-thiadiazol-2-yl
1-thio-b-D-glucopyranoside
(22) was the most efficacious to suppress the blood glucose
excursion during oGT T with the inhibition rates of blood
glucoselevels equal to 74.85% [228].
Since, N-linked glycosides were expected to have greater
metabolic stability compared to O-glucosides, a novel series
of N-linked b-D-xylosides were synthesized and evaluated
for inhibitory activity against SGLT 2 in a cell-based assay.
1354
Among them, the 4-chloroindolyl-N-xyloside with the

4-cyclopropylbenzyl at thedistal position (23) was found the
most potent inhibitor with no selectivity for SGLT 2 over
SGLT 1. According to pharmacokinetic data, compound
(23) was metabolically stable with alow clearanceand good
oral bioavailability in SpragueDawley rats [216].
7.
Conclusion
Morerecently, theneedtodevelopnewdrugs for T 2DM as a

multi-causal andcomplicateddiseasehas been emphasized, as
theworldwideincidenceof this diseaseis increasingdramatically. Various drugoptions arenow availablefor themanagement of T 2DM, but almost all areassociatedwith restrictions
and most do not address all aspects of thedefects in diabetic
patients. T herecently introduced DPP-4 and SGLT 2 inhibitors effectively lower the blood glucose without weight gain
and risk of hypoglycaemia.
T he co-crystal structures of human DPP-4 with some
approvedinhibitors areavailable. So, in recent years, newsyntheticDPP-4 inhibitors with diversechemical structures have
been found, according to the X-ray crystal structure of
DPP-4 and computer-modellingstudies. Remarkablecreativity andthoughts havebeen demonstratedby medicinal chemists in designing novel and potent series of DPP-4 inhibitors.
Various SGLT 2 inhibitors based on theglucosidestructureof
phlorizin, sergliflozin, dapagliflozin, canagliflozin and other
inhibitors in clinical trial havesincebeen proposed. Alternative
candidate SGLT 2 inhibitors that have also been considered
includemodified sugar rings, N-glucosides, S-glucosides, nonglycoside and, more recently, bridged ketal ring, azulene
motifs. T heother promisingagents targetingnovel molecular
mechanisms are under development. T he hope is to discover
more selective and effective anti-diabetic agents in the
near future.
8.
Expert opinion
Despitearapid increasein thenumber of drugs availableto

treat hyperglycaemia, diabetes still remains a major global
concern. Although threeoldest classes comprisinginsulin, sulphonylureas and the biguanides are effective in improving
outcome, they are unable to sustain adequate glycaemic
control over time in the diabetic patients. A variety of antihyperglycaemic drugs with different and complementary
mechanisms of action are currently available. Moreover, the
use of current medications is often limited by their side
effects, mostly sudden hypoglycaemia, weight gain, gastrointestinal effects or oedema. T hesefactors necessitatetheongoing quest for novel agents that would address fundamental
defects of T 2DM and haveminimal adverseeffects.
Among the main anti-diabetic drug classes, DPP-4 and
SGLT 2 inhibitors are novel and promising therapy for
T 2DM. T he details of synthesis backgrounds of many new
DPP-4 inhibitors, in the recent years, are described in this
review. In this review, thestructures of somecompounds with

biological properties are also presented. Phenylalanine and
cyclohexylalanine derivatives and imidazopiperidine-based
b-aminoacidderivatives weredesigned basedon theobservation that modification of thephenylalanine, cyclohexylalanine
or piperazinemoiety improved theDPP-4 potency by several
folds. Also the 3-fluoropyrrolidine analogues obtained by
replacingthepyrrolidinering compounds (1) and (2) showed
more activity compared to parent compound [189,190]. Since
bicyclo[3.3.0]octane derivative with pyrrolidine-2-carbonitrile
was previously reported to beapotent DPP-4 inhibitor [191],
azobicyclo[3.3.0]octanecompounds weresynthesized. T hediscovery of anagliptin was accordingto studies showedthat pyrazolo[1,5-a]pyrimidine functions as a bioisostere conveying
much metabolicstability and safety [193].
A costly component of drug discovery approaches is
structure-basedscreening(docking), which is adesign strategy
for newchemical entities, or optimisation of leadcompounds
identified by other methods, using the 3D structure of the
DPP-4. T he 3D structure of DPP-4 could be obtained by
X-ray or nuclear magneticresonancestudies or from homology models. T he protein data bank is a repository for the
3D structural data of proteins. T he crystal structures of
DPP-4 have been previously disclosed and the discovery of
teneligliptin performedby aidof mentionedin silicomethods
which comprise computationally assessed ligand-binding
interactions with DPP-4. Non-peptidomimetic inhibitors of
DPP-4 such as 3-aminopiperidines with bicycliclactams substituents wereoriginated from sitagliptin --apeptidomimetic
DPP-4 inhibitor, X-ray crystallographic structure along with
molecular modelling [201]. Also non-covalent quinoline-based
inhibitors which target thesidechain of Lys554 weredesigned
based on the X-ray co-crystal structure of some compounds
containing hydrogen bonding interaction with Lys554 [207].
Numerous DPP-4 inhibitors that werediscoveredand/or optimised usingin silicomethods havereached thelevel of clinical
studies or havegained approval of usein somecountries.
Stability and selectivity of SGL T 2 inhibitors is an
important issue in drug design. T he SARs studies of
phlorizin and other candidates led to discovery of another
selectiveand potent SGL T 2 inhibitor with excellent pharmacokinetic properties. Discovery of dioxabicyclo[3.2.1]
octane was supported by analogue-friendly fashion and
PK PD model [222].
T heX-ray crystal structureof SGLT 2 is yet not available;

thus, to explorethestructural requirements for SGLT 2 inhibition, the ligand-directed drug model was used to screen
activecompounds as templates. Ligand-based screeningtechniques mainly focus on comparingmolecular similarity analyses of compounds with known and unknown moiety. T he
3D QSAR methods of CoMFA and CoMSI A models have
been developed as ligand-based approaches. As mentioned,
CoMFA and CoMSI A models weresuccessfully used in providing useful information for designing new SGLT 2 inhibitors [224]. Computer-aided drug design plays an important
role in drug discovery and development and provides useful
insights into experimental findings and mechanism of action
and new suggestions for molecular structures to synthesize.
In this way, large databases of compounds can be tested
in silicowith cheaper and faster techniques beforesubmitting
to in vitroexpensivesynthesis [229].
Most classicanti-diabeticdrugs target themajor pathophysiological defects in T 2DM, namely insulin resistance and
impaired insulin secretion, while the new developing drugs
focus on other options such as SGLT 2 inhibitors that affect
the kidney through insulin-independent mechanisms.
Recently, PPARa/ dual agonists [230], SI RT 1 activators [231,232],
glycogen phosphorylase inhibitors [233] and protein tyrosine
phosphatase 1B inhibitors [233-235] were luckily designed for
thetreatment of T 2DM.
T here is no doubt that T 2DM and its related complications are associated with oxidative stress that plays arole in
thepathogenesis of T 2DM. Antioxidant (natural or synthetic)
therapy can protect b-cells from apoptosis and might positively work in control of hyperglycaemia by activating the
production and releaseof insulin [13,66,74].
Finding new targets and new faster and cheaper synthesis
methods arethemain goal in T 2DM drugdiscovery. Nosingle diabetes treatment is best for everyone as each person
responds in adifferent way tomedication. T ogether, theavailable and rising drug candidates should provide physicians
with abroad rangeof pharmacological choices to successfully
individualisepatient treatment.
Declarat ion of int erest

T heauthors stateno conflict of interest and havereceived no
payment in preparation of this manuscript.
1355
M . Saf avi et al.
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Affiliation
Maliheh Safavi 1, AlirezaForoumadi 1 &
Mohammad Abdollahi 1,2
Author for correspondence

1
T ehran University of Medical Sciences,
Faculty of Pharmacy andPharmaceutical Sciences
Research Center, T ehran, Iran
2
Professor and Dean, T ehran University of
Medical Sciences, Faculty of Pharmacy and
pharmaceutical Sciences Research Center,
Department of T oxicology and Pharmacology,
T ehran 1417614411, Iran
E-mail: Mohammad@T UMS.Ac.Ir
1363

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Review

The import ance of synt het ic drugs

Maliheh Safavi, AlirezaForoumadi & Mohammad Abdollahi

Int roduct ion

Pat hophysiology of T2DM

Overview of current synt het ic

New synt het ic compounds as

New synt het ic compounds as

T ehran University of Medical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences

Diabetes comprises a group of metabolic disorders characterised by chronic

M . Saf avi et al.

Art icle highlight s.

The incidence of T2DM continues to grow rapidly

This box summarises key points contained in the article.

such as coronary artery disease, stroke, hypertension,

Pat hophysiology of T2DM

have not yet been clearly elucidated. For instance, unlike

Expert Opin. Drug Discov. (2013) 8(11)

Import ance of synt het ic drugs f or T2DM drug discovery

Obesity & life

Figure 1. Pat hobiology and t arget s f or current drugs in T2DM .

kinaseC. T hesearethekey signallingmolecules in theactivation of glucoseuptake, inhibition of apoptosis and synthesis

ends up in b-cell exhaustion and finally b-cell failure and

Overview of current synthet ic drugs in t he

Expert Opin. Drug Discov. (2013) 8(11)

M . Saf avi et al.

choice for the treatment of T 2DM due to its good efficacy,

Sulphonylureas as thefast insulin secretagogues aretheoldest

N=lurea insulin secret agogues

Anti-diabetic and insulinotropic properties of the nonsulphonylureamoiety of glibenclamide, subsequently named

Expert Opin. Drug Discov. (2013) 8(11)

Expert Opin. Drug Discov. (2013) 8(11)

Drug st ruct ure

Table 1. Current ant i-diabet ic synt het ic drug classes.

Inhibits intestinal aglucosidase enzymes

Lowers insulin resistance in

Increases insulin secretion in

Stimulates insulin release

Reduces hepatic glucose

M echanism of act ion

Weight gain, fluid retention

Very rare adverse effects

Balfour et al. 1993,

Chachin et al. 2003,

Bharatam et al. 2005,

Import ance of synt het ic drugs f or T2DM drug discovery

Expert Opin. Drug Discov. (2013) 8(11)

Drug st ruct ure

Resets abnormally elevated

Inhibits SGLT2 in the kidneys

Inhibits DPP-4 that improves

M echanism of act ion

Fatigue, nausea, vomiting,

Nausea and vomiting

Nomura et al. 2010,

Gupta et al. 2009,

Wajcberg and Amarah

M . Saf avi et al.

Import ance of synt het ic drugs f or T2DM drug discovery

T roglitazone was the first thiazolidinedione approved as a

T hea-glucosidaseinhibitors acarboseandmiglitol aretwoof

affecting the breakdown of disaccharides to monosaccharides

Glucagon-like pept ide 1 agonists