WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Marvaniya et al. World Journal of Pharmacy and Pharmaceutical Sciences

SJIF Impact Factor 6.647

Volume 6, Issue 8, XXX-XXX Review Article ISSN 2278 – 4357

ROLE OF DIPEPTIDYL PEPTIDASE-IV (DPP-4) INHIBITOR IN THE

MANAGEMENT OF TYPE 2 DIABETES

Hiren M. Marvaniya*1 and Harsha U. Patel2

1
Hemchandracharya North Gujarat University Patan, Gujarat.
2
Shri Sarvajanik Pharmacy College, Mehsana, Gujarat.

Article Received on ABSTRACT

02 June 2017, In the natural history of type 2 diabetes, the development of insulin
Revised on 23 June 2017,
Accepted on 14 July 2017, resistance, impaired glucose tolerance and finally type 2 diabetes
DOI: 10.20959/wjpps20178-9797 occurs gradually over many years: insulin Resistance at peripheral
target tissues and pancreatic beta-cell dysfunction. Insulin sensitivity

*Corresponding Author
declines as an individual moves from normal to impaired glucose
Hiren M. Marvaniya tolerance state. Pancreatic beta cells compensate by hyper-secretion of
Hemchandracharya North insulin in order to maintain normoglycemia. When pancreatic beta
Gujarat University Patan,
cells exhaust and the function of pancreatic beta cells deteriorates
Gujarat.
progressively, an individual progresses from the state of impaired
hirenmarvaniya@gmail.com
fasting glucose or impaired glucose tolerance to frank diabetes. Despite
good compliance to treatment, the glycemic control of type 2 diabetes deteriorates
progressively. Hence, new therapeutic agents are continuously being developed to help our
diabetes population. Recent studies have shown that early intervention at prediabetes state
and beta cell protection with insulin sensitisers may improve the prognosis of diabetes.
Dipeptidyl peptidase-4 (DPP-4) is the enzyme responsible for inactivating the incretin
hormones glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide
(GIP), two hormones that play important roles in glucose homeostasis. Inhibition of
dipeptidyl peptidase 4 is a promising new approach for the treatment of type 2 diabetes. DPP-
4 inhibition results in increased blood concentration of the incretin hormones GLP-1 and GIP.
This causes an increase in glucose-dependent stimulation of insulin secretion, resulting in a
lowering of blood glucose levels. Research has demonstrated that DPP-4 inhibitors portray a
very low risk of hypoglycaemia development. DPP-4 inhibition is safe and well tolerated, the
risk of hypoglycaemia is minimal, and DPP-4 inhibition is bodyweight neutral. This is seen in
association with good tolerability and weight neutrality. Hence, DPP-4 inhibition has the

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Marvaniya et al. World Journal of Pharmacy and Pharmaceutical Sciences

potential to be a novel, efficient and tolerable approach to treat type 2 diabetes. to its solution
form.

KEYWORDS: DPP-4 Inhibitor, Incretin, Vildagliptin, Sitagliptin, Saxagliptin, Type 2

diabetes.

INTRODUCTION[1-2]
In the natural history of type 2 diabetes, the development of insulin resistance, impaired
glucose tolerance and finally type 2 diabetes occurs gradually over many years. It is one of
the fastest growing health concerns in the world. Pancreatic islet cells are initially able to
respond to increased insulin resistance by increasing insulin secretion to maintain
normoglycemia. As the disease develops, however, there is a progressive loss of alpha cell
function. The resultant hyperglycaemia, if left untreated, can eventually lead to the
debilitating vascular complications of type 2 diabetes, including retinopathy, end stage renal
disease, neuropathy and cardiovascular disease. As type 2 diabetes is a progressive disease,
intensification of therapy is normally required over time. While current agents are all
generally effective in the short to medium term, traditional treatment algorithms often fail to
address the progressive nature of the disease. Furthermore, current therapies may also be
associated with an increased risk of hypoglycaemia (sulphonylureas and insulin), weight gain
(sulphonylureas, thiazolidinediones and insulin) and gastrointestinal intolerance (metformin),
which represent major barriers to optimal glycemic control.

Research into the pathophysiology of diabetes has revealed that a complex interplay of
hormonal and neural stimuli, not just insulin and glucagon are involved in the regulation of
plasma glucose levels.

New Approach in Management of T2DM[3-10]

The new approach in management of T2DM is based upon the effects of incretin hormones;
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP),
gastrointestinal hormones released from β-cells of the islets of Langerhans into the
bloodstream primarily in response to meal ingestion. They enhance meal-induced insulin
secretion and play an important part in maintenance of normal glucose homeostasis by a
process termed as incretin effect. GLP-1 has also shown to suppress glucagon secretion, slow
gastric emptying, reduce food intake and body weight.

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In T2DM patients, reduced incretin effect combined with constant decline in pancreatic β and
α -cell function leads to progressive loss of glycemic control. This decline in β and α-cell
function is evident as progressive loss of glucose dependent insulin release and as a
progression to unregulated glucagon production, respectively. In T2DM effects of GLP-1
functions are preserved and in contrast GIP secretion remains normal but with reduced
insulinotropic effect, giving rise to hypothesis that reducing degradation of GLP-1 may
compensate for its decreased secretion in T2DM. However the role of GLP-1 and GIP in
glucose regulation is limited because of their short half life, since they are rapidly degraded
and inactivated by the enzyme dipeptidyl peptidase 4 (DPP-4), resulting in loss of their
insulinotropic activity.

Two approaches have been developed to negate this problem and prolong duration of GLP-1
action. One is the development of long-acting stable analogues of GLP-1, which maintains
the physiologic effect of native GLP-1 but is resistant to action of DPP-4, so-called “Incretin
Mimetics” and second, inhibition of DPP-4 using low molecular weight inhibitors which
decrease the inactivation of GLP-1, thereby increasing its concentration as well as its duration
of action on target tissue, called “Incretin Enhancers”.

Table-1

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This approach was first encapsulated by Holst and Deacon, who showed that DPP-4
inhibition increases circulating levels of GLP-1 in experimental animals and that the
insulinotropic action of exogenously administered GLP-1 is augmented by DPP-4 inhibition.
Later studies demonstrated that the prevention of inactivation of GLP-1 by DPP-4 inhibition
markedly increases the active GLP-1 in the circulation. As a therapeutic application in
T2DM, the prolongation of the endogenous GLP-1 and GIP effect produced by DPP-4
inhibition has several advantages compared with conventional therapies and newer GLP-1
analogues. Also being small molecule DPP-4 inhibitors are orally available and relatively
Oral DPP-4 inhibitors, therefore, represent a potentially important addition to the oral
treatment options currently available for the management of T2DM.

Dipeptidyl peptidase IV (DPPIV), a widely distributed multifunctional type II plasma

membrane glycoprotein, is involved in different biological processes. It is a serine protease
associated with uptake and transmembrane transport of proline-containing peptides as well as
with processing of physiological active peptides1. As an exopeptidase it cleaves N-terminal
dipeptides after proline or alanine residues.

Most DPP-IV inhibitors were designed according to the substrate P1 site structure (occupied
by proline), namely proline-like compounds. Majorities of these are peptide like compounds
and contain cyanopyrrolidine moiety, which forms covalent bond to catalytic residue Ser630
by nitrile group.

CHEMISTRY[11-18]
As a therapeutic class, the DPP-4 inhibitors comprise a diverse group of compounds, which
can be broadly divided into those that mimic the dipeptide structure of DPP-4 substrates and
those which are non-peptidomimetic. Compounds such as sitagliptin (β-amino acid based)
and vildagliptin and saxagliptin, which are nitrilecontaining inhibitors, belong to the former
class, whereas alogliptin (modified pyrimidinedione) and linagliptin (xanthine-based) are
members of the latter (figure 1, Table 1). The compounds which have been developed for
therapeutic use are all competitive reversible inhibitors, which display high affinity for DPP-
4, resulting in inhibition constants (Ki) in the low nanomolar range. There are, however,
differences in the way in which they interact with the enzyme Thus, sitagliptin, alogliptin and
linagliptin form non-covalent interactions with residues in the catalytic site. In contrast,
inhibition of DPP-4 by vildagliptin and saxagliptin has been described as a two-step process
that involves the formation of a reversible covalent enzyme–inhibitor complex in which there

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is a slow rate of inhibitor binding and a slow rate of inhibitor dissociation, resulting in the
enzyme slowly equilibrating between the active and inactive forms. This means that the
catalytic activity will be inhibited even after the free drug has been cleared from the
circulation and may help to explain why vildagliptin and saxagliptin inhibit DPP-4 activity
for longer than their relatively short half lives would suggest. This may have repercussions in
terms of their durations of action and dosing frequencies (see below).

Table-2 Chemistry, Metabolism and Elimination of DPP-4 inhibitors

Table-3 Half life, Potency (dose) and DPP-4 inhibitory efficacy of DPP-4 inhibitors

Structure of DPP-4[19-24]
X-ray structures of DPP-4 give detailed information about the structural characteristics of the
binding site. Many structurally diverse DPP-4 inhibitors have been discovered and it is not
that surprising while considering the properties of the binding site.

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1. A deep lipophilic pocket combined with several exposed aromatic side chains for
achieving high affinity small molecule binding.

2. A significant solvent access which makes it possible to tune the physico-chemical

properties of the inhibitors that leads to better pharmacokinetic behaviour.

DPP-4 is a 766 amino acid transmembrane glycoprotein which belongs to the prolyl
oligopeptidase family. It consists of three parts; a cytoplasmic tail, a transmembrane region
and an extracellular part. The extracellular part is divided into a catalytic domain and an
eight-bladed β-propeller domain. domain shows α/β-hydrolase fold and contains the catalytic
triad Ser630 - Asp708 - His740. The S1-pocket is very hydrophobic and is composed of the
side chains: Tyr631, Val656, Trp662, Tyr666 and Val711. Existing X-ray structures show
that there is not much difference in size and shape of the pocket that indicates that the S1-
pocket has high specificity for proline residues.

Binding site
DPP-4 inhibitors usually have an electrophilic group that can interact with the hydroxyl of the
catalytic serine in the active binding site (Fig. 1). Frequently that group is a nitrile group but
can also be boronic acid or diphenyl phosphonate.

Figure 1: The key interactions between the ligand and DPP-4 complex. The ligand's
basic amine forms a hydrogen bonding network. The nitrile reacts with the catalytic
active serine and forms an imidate adduct.

This electrophilic group can bind to the imidate complex with covalent bonds and slow tight-
binding kinetics but this group is also responsible for stability issues due to reactions with the

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free amino group of the P2-amino acid. Therefore, inhibitors without the electrophilic group
have also been developed, but these molecules have shown toxicity due to affinity to other
dipeptidyl peptidases, e.g. DPP-2, DPP-8 and DPP-9.

DPP-4 inhibitors span diverse structural types. In 2007 few of the most potent compounds
contain a proline mimetic cyanopyrrolidine P1 group. This group enhances the potency,
probably due to a transient covalent trapping of the nitrile group by the active site Ser630
hydroxyl, leading to delayed dissociation and slow tight-binding of certain inhibitors. When
these potency enhancements were achieved, some chemical stability issues were noted and
more advanced molecules had to be made. To avoid these stability issues, the possibility to
exclude the nitrile group was investigated. Amino acids with aryl or polar side chains did not
show appreciable DPP-4 inhibition and in fact, all compounds without the nitrile group in this
research suffered a 20 to 50-fold loss of potency corresponding to the compounds containing
the nitrile group.

Discovery and Development of DPP-4 Inhibitors[25-37]

It is important to find a fast and accurate system to discover new DPP-4 inhibitors with ideal
therapeutic profiles. High throughput screening (HTS) usually gives low hit rates in
identifying the inhibitors but virtual screening (VS) can give higher rates. VS has for example
been used to screen for small primary aliphatic amines to identify fragments that could be
placed in S1 and S2 sites of DPP-4. On the other hand, these fragments were not very potent
and therefore identified as a starting point to design better ones. 3D models can provide a
useful tool for designing novel DPP-4 inhibitors. Pharmacophore models have been made
based on key chemical features of compounds with DPP-4 inhibitory activity. These models
can provide a hypothetical picture of the primary chemical feature responsible for inhibitory
activity. The first DPP-4 inhibitors were reversible inhibitors and came with bad side effects
because of low selectivity. Researchers suspected that inhibitors with short half-lives would
be preferred in order to minimize possible side effects. However, since clinical trials showed
the opposite, the latest DPP-4 inhibitors have a long-lasting effect. One of the first reported
DPP-4 inhibitor is P32/98 from Merck. It used thiazolidide as the P1-substitute and is the first
DPP-4 inhibitor that showed effects in both animals and humans. Another old inhibitor is
DPP-728 from Novartis, where 2-cyanopyrrolidine is used as the P1-substitute. The addition
of the cyano group generally increases the potency. Usually, DPP-4 inhibitors are either
substrate-like or nonsubstrate- like.

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a. Substrate-like inhibitors
Substrate-like inhibitors (Fig. 2) are more common than the non-substrate-likes. They bind
either covalently or noncovalently and have basic structure where the P1-substituent occupies
the S1-pocket and the P2-substituent occupies the S2-pocket. Usually they contain a proline
mimetic that occupies the S1-pocket. Large substituents on the 2- cyanopyrrolidine ring are
normally not tolerated since the S1- pocket is quite small. Since DPP-4 is identical with the
T-cell activation marker CD26 and DPP-4 inhibitors are known to inhibit T-cell proliferation,
these compounds were initially thought to be potential immunomodulators. When the
function against type 2 diabetes was discovered, the cyanopyrrolidines became a highly
popular research material. A little later vildagliptin and saxagliptin, which are the most
developed cyanopyrrolidine DPP-4 inhibitors to date, are discovered.

Figure 2: A generic structure of a substrate-like inhibitor.

Cyanopyrrolidines
Cyanopyrrolidines have two key interactions to the DPP-4 complex
1. Nitrile in the position of the scissile bond of the peptidic substrate is important for high
potency. The nitrile group forms reversible covalent bonds with the catalytically active serine
hydroxyl (Ser630), i.e. cyanopyrrolidines are competitive inhibitors with slow dissociation
kinetics.

2. Hydrogen bonding network between the protonated amino group and a negatively charged
region of the protein surface, Glu205, Glu206 and Tyr662. All cyanopyrrolidines have basic,
primary or secondary amine which makes this network possible but these compounds usually
drop in potency if these amines are changed. Nonetheless, two patent applications unveil that
the amino group can be changed, i.e. replaced by a hydrazine, but it is claimed that these
compounds do not only act via DPP-4 inhibition but also prevent diabetic vascular
complications by acting as a radical scavenger.

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Important structure-activity relationship studies shows that

1. Strict steric constraint exists around the pyrrolidine ring of cyanopyrrolidine-based
inhibitors, with only hydrogen, fluoro, acetylene, nitrile or methano substitution.

2. Presence of a nitrile moiety on the pyrrolidine ring is critical to achieving potent activity.
Also, systematic structure activity relationship investigation has shown that the ring size and
stereochemistry for the P2 position is quite conditioned. A 5-membered ring and L-
configuration has shown better results than a 4-membered or 6-membered ring with
Dconfiguration. Only minor changes on the pyrrolidine ring can be tolerated since the good
fit ofthe ring with the hydrophobic S1 pocket is very important for high affinity. Some trials
have been made, e.g. by replacing the pyrrolidine with a thiazoline. That led to improved
potency but also loss of chemical stability. Efforts to improve chemical stability often led to
loss of specificity because of interactions with DPP-8 and DPP-9. These interactions have
been connected with increased toxicity and mortality in animals. There are strict limitations
in the P1 position and hardly any changes are tolerated, on the other hand a variety of
changes can be made in the P2 position. In fact, substitution with quite big branched side
chains, e.g. tert-butylglycin, normally increased activity and chemical stability which could
lead to longer-lasting inhibition of the DPP-4 enzyme. It has also been noted that biaryl-based
side chains can also give highly active inhibitors. Originally it was believed that only
lipophilic substitution would be tolerated; now it.s stated that also the substitution of polar
negatively charged side chains as well as hydrophilic substitution can lead to excellent
inhibitory activity

Chemical stability
DPP-4 inhibitors generally are not very stable compounds. Therefore, many researchers focus
on enhancing the stability for cyanopyrrolidines. The most widespread technique to improve
chemical stability is to incorporate a steric bulk. The two cyanopyrrolidines that have been
most pronounced, vildagliptin and saxagliptin, were created in this manner. K579 is a DPP-4
inhibitor discovered by researchers at Kyowa Hakko Kyogo. It does not only have improved
chemical stability but also a longer -lasting action. That longlasting action is due to slow
dissociation of the enzymeinhibitor complex and an active oxide metabolite that undergoes
enterohepatic circulation. The discovery of the active oxide was in fact a big breakthrough as
it led to the development of vildagliptin and saxagliptin

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Figure 3: Trans-rotamers are more stable then cis-rotamers. cis-rotamers undergo

intramolecular cyclisation.

One major problem in DPP-4 inhibitor stability was intramolecular cyclisation. The
precondition for the intramolecular cyclisation is the conversion of the transrotamer, which is
the DPP-4 binding rotamer (Fig. 3). Thus, preventing this conversion will increase stability.
This prevention was successful when incorporating an amide group into a ring, creating a
compound that kept the DPP-4 inhibitory activity that didn.t undergo the intramolecular
cyclisation and was even more selective over different DPP enzymes. It has also been
reported that a cyanoazetidine in the P1 position and a alpha amino acid in the P2 position
increased stability.

Vildagliptin: Vildagliptin (Fig.4) was first synthesized and discovered by Novartis in May
1998. Researchers examined adamantly derivatives to be very potent. The adamantyl group
worked as a steric bulk and slowed intramolecular cyclization with increasing chemical
stability. Furthermore, the primary metabolites were highly active. To avoid additional chiral
center a hydroxylation at the adamantyl ring was carried out (Fig. 3). The product,
vildagliptin, was even more stable, undergoing intramolecular cyclisation 30-times slower,
and having high DPP-4 inhibitory activity and longer-lasting pharmacodynamic effect.

Figure 4: The basic structure of cyanopyrrolidines compared with vildagliptin,

saxagliptin and denagliptin.

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Saxagliptin
With increased steric bulk of the N-terminal amino acid side chain led to increased stability.
To increase stability the transrotamer with a cis-4,5-methano substitution of the pyrrolidine
ring, results in intramolecular van-der-Waals interaction, thus preventing intramolecular
cyclisation. Because of this increased stability, the researchers continued their investigation
on cis-4,5-methano cyanopyrrolidines and came across with a new adamantyl derivative
which showed extraordinary ex vivo DPP-4 inhibition in rat plasma. After hydroxylation on
the adamantyl group they had a product with better microsomal stability and improved
chemical stability. That product was named saxagliptin (Fig 4).

Denagliptin
Denagliptin (Fig. 4) an advanced compound with a branched side chain at the P2 position, but
also has (4S)-fluoro substitution on the cyanopyrrolidine ring.[9] It is a well known DPP-4
inhibitor developed by GlaxoSmithKline. Biological evaluations have shown that the S-
configuration of the amino acid portion is essential for the inhibitory activity since the
Rconfiguration showed reluctantly inhibition. These findings are useful in future for
designing and synthesis of DPP-4 inhibitors.

Azetidine based compounds: Azetidine-based DPP-4 inhibitors can roughly be grouped into
three main subcategories; 2-cyanoazetidines, 3- fluoroazetidines and 2-ketoazetidines. The
most potent ketoazetidines and cyanoazetidines have large hydrophobic amino acid groups
bound to the azetidine nitrogen and are active below 100nM.

b. Non-substrate-like inhibitors
Non-substrate-like inhibitors are non-covalent inhibitors and usually have an aromatic ring
that occupies the S1-pocket, instead of the proline mimetic.[14] In 1999, Merck started a drug
development program on DPP-4 inhibitors. When they started internal screening and
medicinal chemistry program, two DPP-4 inhibitors were already in clinical trials, isoleucyl
thiazolidide (P32/38) and NVP-DPP728 from Novartis. Merck licensed L-threo-isoleucyl
thiazolidide and its allo stereoisomer. In animal studies, they found that both isomers have
similar affinity for DPP-4, similar in vivo efficacy, similar pharmacokinetic and metabolic
profiles. Nevertheless, the allo isomer was 10-fold more toxic. The researchers found out that
this difference in toxicity was due to the allo isomer's greater inhibition of DPP-8 and DPP-9
but not because of selective DPP-4 inhibition. More research also supported that DPP-4
inhibition would not cause compromised immune function. Once this link between affinity

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for DPP-8/DPP-9 and toxicity was discovered, Merck decided on identifying an inhibitor
with more than a thousandfold affinity for DPP-4 over the other dipeptidases. For this
purpose they used positional scanning libraries. From scanning these libraries, both DPP-4
and DPP-8 showed a strong preference for breaking down peptides with a proline at the P1
position but they found a great difference at the P2 site, i.e. they found that acidic
functionality at the P2 position could provide a greater affinity for DPP-4 over DPP-8. Merck
kept up doing even more research and screening. They stopped working on compounds from
the á-amino acid series related to isoleucyl thiazolidide due to lack of selectivity but instead
they discovered a very selective â-amino acid piperazine series through SAR studies on two
screening leads. When trying to stabilize the piperazine moiety, a group of bicyclic
derivatives were made, which led to the identification of a potent and selective
triazolopiperazine series. Most of these analogs showed excellent pharmacokinetic properties
in preclinical species. Optimization of these compounds finally led to the discovery of
sitagliptin.

Sitagliptin

Figure 5: The structure of sitagliptin.

Sitagliptin has a novel structure with â-amino amide derivatives (Fig. 5). Since sitagliptin has
shown excellent selectivity and in vivo efficacy it urged researches to inspect the new
structure of DPP-4 inhibitors with appended â-amino acid moiety. Further studies are being
developed to optimize these compounds for the treatment of diabetes. Crystallographic
structure of sitagliptin along with molecular modeling has been used to continue the search
for structurally diverse inhibitors. A new potent, selective and orally bioavailable DPP-4
inhibitor was discovered by replacing the central cyclohexylamine in sitagliptin with 3-
aminopiperidine.

A 2-pyridyl substitution was the initial SAR breakthrough since that group plays a significant
role in potency and selectivity for DPP-4.

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It has been shown with an X-ray crystallography how sitagliptin binds to the DPP-4 complex
1. The trifluorophenyl group occupies the S1-pocket
2. The trifluoromethyl group interacts with the side chains of residues Arg358 and Ser209.
3. The amino group forms a salt bridge with Tyr662 and the carboxylated groups of the two
glutamate residues, Glu205 and Glu206.
4. The triazolopiperazine group collides with the phenyl group of residue Phe357

Constrained phenylethylamine compounds

Researchers at Abbott Laboratories identified three novel series of DPP-4 inhibitors using
HTS. After more research and optimization ABT-341 was discovered (Fig. 6). It is a potent
and selective DPP-4 inhibitor with a 2D-structure very similar to sitagliptin. However, the
3D-structure is quite different. ABT-341 also has a trifluorophenyl group that occupies the
S1-pocket and the free amino group, but the two carbonyl groups are orientated 180° away
from each other. ABT-341 is also believed to interact with the Tyr547, probably because of
steric hindrance between the cyclohexenyl ring and thetyrosine side chain.[40]

Alogliptin

Figure 7: Quinazolinone structure and alogliptin

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Pyrrolidine compounds
The pyrrolidine types of DPP-4 inhibitors are discovered after HTS. Research showed that
the pyrrolidine rings are the part of the compounds that fit into the binding site. Further
development has led to fluoro substituted pyrrolidines that showed superior activity, as well
as pyrrolidines with fused Cyclopropylrings are highly active.

Xanthine-based compounds: This is different class of inhibitors that are identified with
HTS. When xanthine based DPP-4 inhibitors are compared with sitagliptin and vildagliptin it
has shown a superior profile. Xanthines are believed to have higher potency, longerlasting
inhibition and longer-lasting improvement of glucose tolerance.

Alogliptin: Alogliptin (Fig. 7) is a novel DPP-4 inhibitor developed by the Takeda

Pharmaceutical. Quinazolinone based structure have the necessary groups to interact with the
active site on the DPP-4 complex. Quinazolinone based compounds interact effectively with
the DPP-4 complex, but suffered from low metabolic half-life. It is found that when replacing
the quinazolinone with a pyrimidinedione, the metabolic stability is increased and the results
are potent, selective, bioavailable DPP-4 inhibitor named alogliptin. The quinazoline based
compounds shows potent inhibition and excellent selectivity over related protease, DPP-8.
However, short metabolic halflife due to oxidation of the A-ring phenyl group is problematic.
At first, the researchers tried to make a fluorinated derivative. The derivative shows improved
metabolic stability and excellent inhibition of the DPP-4 enzyme. Alogliptin is discovered
when quinazolinone is replaced with a pyrimidinedione. Alogliptin has shown excellent
inhibition of DPP-4 and extraordinary selectivity, greater than 10.000 fold over the closely
related serine proteases DPP-8 and DPP-9. Also, it does not inhibit the CYP450 enzymes nor
block the hERG (human Ether RelatedGene) channel at concentration up to 30µM.

Figure 8: Xanthine type inhibitors and the potent candidate, BI-1356.

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By using a buty-2-nyl group a potent candidate, called BI-1356 is discovered (Fig. 8). In
2008 BI-1356 underwent phase III clinical trials. X-ray crystallography has shown that
xanthine type binds the DPP-4 complex in a different way than other inhibitors

1. The amino group also interacts with the Glu205, Glu206 and Tyr662
2. The buty-2-nyl group occupies the S1-pocket
3. The uracil group undergoes a ð-stacking interaction with the Tyr547 residue
4. The quinazoline group undergoes a ð-stacking interaction with the Trp629 residue

CONCLUSION
DPP-4 inhibitors are promising new medicines for the treatment of type 2 diabetes mellitus.
They are supposed to improve metabolic control (as measured by lowering blood glucose)
without causing severe hypoglycemia. DPP-4 inhibitors as monotherapy may not be
sufficiently active in patients with poor and longstanding disease so combination therapy with
metformin, sulfonylureas, and thiazolidinedionesis also suggested. Since the new DPP-4
inhibitors may influence immune function so additional long-term data on the safety of these
drugs are necessary. Also, cardiovascular outcomes like heart attacks and strokes should not
be increased with any antidiabetic therapy. Based on the current evidence, these agents
represent viable second-and third-line options in the management of type 2 diabetes. With the
rising prevalence of diabetes, new therapies that provide glucose control are needed.
Although many medications are available, tight glucose control is still a challenge.

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