European Journal of Medicinal Chemistry 151 (2018) 145e157

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European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech

Mini-review

Recent progress of the development of dipeptidyl peptidase-4

inhibitors for the treatment of type 2 diabetes mellitus
Ning Li a, b, c, d, Li-Jun Wang a, b, d, Bo Jiang a, b, d, Xiang-qian Li a, b, d, Chuan-long Guo a, b, c, d,
Shu-ju Guo a, b, d, Da-Yong Shi a, b, c, d, *
a
Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
b
Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
c
University of Chinese Academy of Sciences, Beijing, China
d
Center for Ocean Mega-Science, Chinese Academy of Sciences, China

a r t i c l e i n f o a b s t r a c t

Article history: Diabetes is a fast growing chronic metabolic disorder around the world. Dipeptidyl peptidase-4 (DPP-4)
Received 15 December 2017 is a new promising target during type 2 diabetes glycemic control. Thus, a number of potent DPP-4
Received in revised form inhibitors were developed and play a rapidly evolving role in the management of type 2 diabetes in
14 March 2018
recent years. This article reviews the development of synthetic and natural DPP-4 inhibitors from 2012 to
Accepted 14 March 2018
Available online 21 March 2018
2017 and provides their physico-chemical properties, biological activities against DPP-4 and selectivity
over dipeptidyl peptidase-8/9. Moreover, the glucose-lowering mechanisms and the active site of DPP-4
are also discussed. We also discuss strategies and structure-activity relationships for identifying potent
Keywords:
DPP-4
DPP-4 inhibitors, which will provide useful information for developing potent DPP-4 drugs as type 2
Inhibitors diabtes treatments.
Analogs © 2018 Elsevier Masson SAS. All rights reserved.
Physico-chemical properties
SARs
Type 2 diabetes

1. Introduction insulin delivery (insulin analogs) are extensively used. Currently a-

Diabetes is a fast growing chronic metabolic disorder around the
world. According to the newest data of the International Diabetes
Federation (IDF), about 425 million adults had diabetes for 2017,
and the number will rise to 700 million in 2045 [1]. The risks of
many micro- and macro-vascular complications such as stroke,
retinopathy, neuropathy, nephropathy, coronary artery disease,
hypertension and peripheral vascular disease are increased due to
type 2 diabetes mellitus (T2DM) [2]. T2DM is mainly characterized
by insulin resistance and insulin deficiency. The ultimate aim
behind T2DM treatment is to lower and maintain glycosylated
haemoglobin level below 7% and therefore to prevent the risk of
micro- and macro-vascular complications associated with the dis-
ease [3]. To reduce blood glucose levels and the risks associated
with T2DM, biguanides, insulin sensitisers (thiazolidinediones),
insulin secretagogues (sulphonylureas; meglitinides) and external
* Corresponding author. Key Laboratory of Experimental Marine Biology, Institute
of Oceanology, Chinese Academy of Sciences, Qingdao, China.
E-mail address: shidayong@qdio.ac.cn (D.-Y. Shi).
glucosidase inhibitors, glucagon-like peptide-1 (GLP-1) agonists,
sodium-dependent glucose transporters 2 inhibitors and the
recently introduced dipeptidyl peptidase-4 (DPP-4) inhibitors are
approved by Drug Administration or European Medicines Agency
[4].
DPP-4 (CD26, EC 3.4.14.5) is a serine peptidase expressed as a
220 kDa homodimeric type II transmembrane glycoprotein on the
surface of various cell types [5]. It is widely expressed in most tis-
sues, including the kidney, gastrointestinal tract, biliary tract and
liver, placenta, uterus, prostate, skin and lymphocytes [6].
DPP-4 is involved in rapidly inactivating both GLP-1 and
glucose-dependent insulinotropic polypeptide (GIP), therefore
prolonging half-life of GLP-1 (less than 2 min) and GIP (about
2e3 min) [7]. GLP-1 is a 30-amino acid peptide hormone made in
the intestinal epithelial endocrine L-cells [8] and GIP consists of 42
amino acids secreted predominantly in duodenal K cells in the
proximal small intestine [9]. The main actions of GLP-1 and GIP are
to increase insulin biosynthesis, to promote beta cell proliferation
and to reduce beta cell apoptosis, contributing to limiting post-
prandial glucose excursions. Therefore the mechanism of anti-

https://doi.org/10.1016/j.ejmech.2018.03.041
0223-5234/© 2018 Elsevier Masson SAS. All rights reserved.
146 N. Li et al. / European Journal of Medicinal Chemistry 151 (2018) 145e157
hyperglycemic effect of DPP-4 inhibitors is associated with GLP and
GIP.
It has been reported that DPP-4 inhibitors prevent the inacti-
vation of the incretin hormone GLP-1, which contributes to insulin
secretion stimulation, glucagon secretion inhibition and thereby
glucose control improvement. This is a kind of glucose-dependent
manner explaining the low risk of hypoglycaemia associated with
DPP-4 inhibitors [10]. However, presented ~50% of the glucose
lowering effect of DPP-4 inhibitor treatment in humans was
blocked by the GLP-1 receptor antagonist exendin (9e39) [11].
Although the effects of sitagliptin on glucagon and gastric emptying
were abolished by GLP-1 receptor blockade, a partial but consid-
erable effect on glucose-lowering and insulinotropic actions was
maintained. This suggested that DPP-4-sensitive factors beyond
circulating GLP-1 substantially contribute to the incretin effect
during glycemic control. Moreover, a study reported by Nauck et al.
[12] suggested that not all insulinotropic effects introduced by DPP-
4 inhibition (vildagliptin treatment) in subjects with T2DM are
mediated by GLP-1. It is consistent with, and complimentary to,
outcomes previously reported by Aulinger et al [11]. A particularly
large increase in bioactive GIP levels in humans treated with DPP-4
inhibitors, which supported the notion that increased GIP bioac-
tivity significantly contributes to the therapeutic benefit of DPP-4
therapy [13]. It suggested a significant DPP-4-sensitive incretin
effect that contributes to glycemic control in T2DM patients may be
not only mediated by circulating GLP-1, DPP-4 inhibitor treatment
may have a much greater impact on plasma bioactive GIP levels
than bioactive GLP-1 levels in healthy subjects. On the other hand,
the rate of gastric emptying is also associated with the efficacy of
DPP-4 inhibition in reducing postprandial glycemia reported by Wu
et al. [7,14].
Scheen et al. [15] and Omar et al. [16] have ever reviewed the
mechanisms for the glucose-lowering action of DPP-4 inhibitors,
including classical mechanisms and pleiotropic mechanisms.
Briefly, the mechanisms for the glucose-lowering action of DPP-4
inhibitors include GLP-1edependent and GLP-1eindependent
mechanisms. Apart from GLP-1, other four possible bioactive pep-
tides were presented by Nauck et al. [12]: GIP, oxyntomodulin, pi-
tuitary adenylate cyclaseeactivating peptide, and stromal
cellederived factor-1a [17,18]. Still, the exact GLP-1eindependent
mechanisms remain to be fully understood (Fig. 1).
In this review, we have summarized the development of syn-
thetic and natural DPP-4 inhibitors from 2012 to 2017 and their
physico-chemical properties, biological activities against DPP-4 and
Fig. 1. Mechanisms for the glucose-lowering action of DPP-4 inhibitors.
selectivity against dipeptidyl peptidase-8 (DPP-8) and dipeptidyl
peptidase-9 (DPP-9). We also discussed strategies and structure-
activity relationships (SARs) for identifying potent DPP-4 in-
hibitors which provide useful information for developing potent
DPP-4 drugs as type 2 diabetes treatments.
2. Marketed DPP-4 inhibitors
The idea of inhibiting DPP-4 was suggested as a potential new
therapy for T2DM 20 years ago [19]. It became available in 2006.
Currently, there are at least 12 DPP-4 inhibitors that have already
been approved on the market, as shown in Table 1. Sitagliptin [20]
was the first DPP-4 inhibitor, granted by FDA followed by vilda-
gliptin [21], saxagliptin [22], alogliptin [23] and linagliptin [24].
New members continue to be approved: anagliptin [25], gem-
igliptin [26], teneligliptin [27] in 2012; evogliptin [28], omarigliptin
[29] and trelagliptin [30] in 2015, gosogliptin [31] in2016 (Fig. 2).
Among these drugs, both trelagliptin and omarigliptin are novel
once-weekly dipeptidyl peptidase 4 inhibitors. In addition, trela-
gliptin and omarigliptin were superior to placebo and similar to
DPP-4 inhibitors administered once-weekly in terms of glycemic
control, and were not associated with any specific adverse events
[32].
3. Synthetic DPP-4 inhibitors
3.1. The peptidomimetic series
2-Cyano pyrrolidine derivatives are reported as potent and se-
lective DPP-4 inhibitors for the treatment of T2DM. Compounds 1
(2.3 ± 0.9 nM) and 2 (3.8 ± 0.5 nM) showed excellent in vitro po-
tency and selectivity towards DPP-4; moreover, compound 1
demonstrated sustained suppression of pre- and post-prandial
blood glucose levels (in vivo), which correlated with its extended
pharmacokinetic profile [33]. Compound 3 (3.79 nM), synthesized
and evaluated by Liu et al. [34], exhibited potent DPP-4 activity and
moderate selectivity against DPP-4 over other related enzymes
including dipeptidyl peptidase-7 (DPP-7), DPP-8, and DPP-9. In
addition, compound 3 can reduce blood glucose excursion in an
oral glucose tolerance test in normal Sprague Dawley rats. SAR
studies of 2-Cyano pyrrolidine derivatives showed that cyano-
pyrrolidine was crucial for inhibitory activity, since it formed
hydrogen bonds with OH-group of side-chain of Ser630 and
carbonyl of side-chains of Glu205 and Glu206. Moreover, the
 N. Li et al. / European Journal of Medicinal Chemistry 151 (2018) 145e157 147

Table 1
The family of commercial dipeptidyl peptidase-4 inhibitors.

DPP-4 inhibitor release year brand name Country t1/2(h)a

Sitagliptin 2006 zanuvia Worldwide 8e24

Vildagliptin 2007 Galvus Worldwide 1.5e4.5
Excluding America
Saxagliptin 2009 Onglyza Worldwide 2-4 (parent)
Alogliptin 2010 Vipidia,Nesina Worldwide 21.1
Linagliptin 2011 Tradjenta,Trajenta Worldwide 10e40
Trazenta
Anagliptin 2012 suiny Japan 5.8e6.2
Gemigliptin 2012 Zemiglo South Korea, 16.7e21.3
IIndia
Teneligliptin 2012 Tenelia Japan, India 26.9
South Korea,
Evogliptin 2015 Suganon South Korea 32.5e39.8
Omarigliptin 2015 Marizev Japan 11e22
Trelagliptin 2015 Zafatek Japan 38.44e54.26
Gosogliptin 2016 satyor Russian Federation 63.5 (parent)
a
The elimination half-life of commercial dipeptidyl peptidase-4 inhibitors.

enhanced binding affinity was explained by strong hydrogen bond
between benzamide/triazole and Arg358, and p-p interaction be-
tween the benzyl group and Phe357.
Later, fluorinated pyrrolidine amides were found to exhibit
potent DPP-4 inhibitory activities. Compounds 4 (0.004 mM) and 5
(0.01 mM) demonstrated excellent inhibitory activities against DPP-
4, with good selectivity, good efficacy in an oral glucose tolerance
test (OGTT) in ICR mice (Institute of Cancer Research mice) and
moderate pharmacokinetics properties [35]. Most of the com-
pounds exhibited good in vitro potency against DPP-4 reported by
Zhang et al. [36]. Among these, compounds 6 (1.32 mM), 7
(0.66 mM), and 8 (0.72 mM) displayed good DPP-4 activity and
excellent selectivity versus other proteases including DPP-8, DPP-9,
and Fibroblast Activation Protein (FAP). Molecular docking studies

Fig. 2. Marketed DPP-4 inhibitors.

148 N. Li et al. / European Journal of Medicinal Chemistry 151 (2018) 145e157
suggested that the difluoropyrrolidide moiety made extensive hy-
drophobic interactions with the side chains of Trp659, Val 656,
Val711, Tyr631, Ser630, Tyr666, and Tyr662.
Other glycine-based DPP-4 inhibitors were synthesized and
evaluated. Zhao et al. [37] presented a series of piperidine de-
rivatives as DPP-4 inhibitors, compound 9 (Ki ¼ 10 nM) showed the
highest potency against the enzyme of DPP-4.
Series of pyrrolidine-based inhibitors have synthesized and
evaluated for their DPP-4 inhibitory activity. Compound 10
(0.37 nM) is the most potent, long-lasting DPP-4 inhibitor with high
selectivity against other related peptidases [38]. The SAR analysis of
10 indicated that quinolyl ring contributed to inhibitory activity
which was stacked with the side chain of Phe357 in the S2 subsite.
Another group on the quinolyl ring, trifluoromethyl, also interacted
with Tyr585. Compound 11 (3.73 mM) showed better in vitro
inhibitory activity than reference inhibitor P32/98 and moderate
in vivo antihyperglycemic, antidyslipidemic, and insulin resistance
reversal activities compared to standard antidiabetic drug, Sita-
gliptin [39]. SAR studies of compound 11 showed that 7-
chloroquinolin moiety was crucial for inhibitory activity, since it
Fig. 3. The peptidomimetic series.
was stacked with the side chain of Phe357 via a p-p interaction and
also stabilized with hydrophobic residues such as Ser209, Arg358,
Phe357. Moreover, the enhanced binding affinity was explained by
strong hydrogen bond between the carbonyl group of the amide
bond and the side chains of Asn710 and Arg125. Compound 12
(94.82 nM) was found to be potent DPP-4 inhibitor among all the
molecules synthesized in series [40]. Compound 13 (2.12 mM) and
14 (3.44 mM) exhibited the modest activity against DPP-4 [41]. In
addition, series of compounds were evaluated for their inhibitory
activity toward DPP-4 [42]. Among them, compound 15 (6.93 nM),
16 (6.29 nM) and 17 (3.4 nM) showed good inhibitions of DPP-4 in
virto, furthermore, compound 17 exhibited better hypoglycemic
ability in vitro than the other two compounds.
Apart from the a-series, the b series also play an important role
in discovering novel inhibitors of DPP-4. Nitta et al. [43] have re-
ported a series of b-alanine-based inhibitors as DPP-4 inhibitors.
Among them, oral administration of compound 18 (0.016 mM)
exhibited potent DPP-4 inhibitory activity and selectivity against
the other proteases and reduced the blood glucose excursion in
OGTT (Fig. 3).
 N. Li et al. / European Journal of Medicinal Chemistry 151 (2018) 145e157
3.2. Non-peptidomimetic DPP-4 inhibitors
3.2.1. Xanthine analogs
Xanthine scaffold has specific advantages related to DPP-4 in-
hibition. Ikuma et al. [44] reported the discovery of a novel potent
DPP-4 inhibitor with 3H-imi-dazo [4,5-c]quinolin-4(5H)-one as
skeleton. Compound 19 (0.48 nM) showed strong DPP-4 inhibitory
activity compared to marketed DPP-4 inhibitors with excellent
selectivity against various DPP-4 homologues. Series of compounds
were synthesized and evaluated for their inhibitory activity toward
DPP-4 [45]. Among them, compound 20 (36 nM) exhibited com-
parable activity with a positive control, Sitagliptin (16 nM). Xie et al.
[46] identified several series of xanthine analogs as DPP-4 in-
hibitors derived from Alogliptin using multiple classic medicinal
chemistry strategies. Compound 21 (1.4 nM) presented greater
in vivo efficacy than Alogliptin (3.4 nM) which is worthy of further
development. Compound 22 (19.6 nM) exhibited a good in vivo
efficacy in reducing glucose excursion at a single dose and a better
chronic effect in reducing body weight than metformin in diet-
induced obesity mice (DIO mice) [47]. In addition, Ran et al. [48]
discovered (R)-22 exhibited moderate antihyperglycemic activity
as compared to the standard antidiabetic drug Linagliptin in oral
glucose tolerance tests and effectively improved the pathological
state of DIO mice combining the hypoglycemic with hypolipidemic
effects. Similarly, compound 23 (1.55 nM) showed significantly
improved pharmacokinetic properties [49]. Shu et al. [50] also
discovered a novel series of potent and selective DPP-4 inhibitors,
compound 24 or Imigliptin (9 nM) as a clinical candidate. Currently,
Imigliptin is under clinical development in China after it got China
Food and Drug Administration regulatory approval. Various series
of novel pyrazolo [3,4-d]pyrimidinones as DPP-4 inhibitors in dia-
betes were reported by Sagar et al. [51]. Amongst all the synthe-
sized compounds, 25 (1.06 ± 0.09 nM) was found to be the most
active based on in vitro DPP-4 studies and also exhibited promising
in vivo blood glucose lowering activity in male Wistar rats.
Fig. 4. Xanthine analogs.
149
Compound 26 (0.5 nM) displayed an improved in vitro and ab-
sorption, distribution, metabolism and excretion profile [52].
Another compound 27 (0.22 mM) showed selective DPP-4 inhibi-
tion, good G protein-coupled receptor 119 agonism activity and
favorable metabolic stability [53]. SAR studies of xanthine analogs
showed that the xanthine moiety formed aromatic p-stacking in-
teractions with the phenol of Tyr547 and a hydrogen bond with the
backbone NH of Tyr631; Benzyl side moiety was necessary since p-
stacking interactions were observed with its surrounding residues
Trp659 and Tyr666; the 2-cyanobenzyl substituent functioned as
an H-bond acceptor to Arg125. Moreover, the aminopiperidine
formed an essential salt bridge with the backbone carboxylate of
Glu205 and Glu206 in the S2 pocket, which was crucial for inhib-
itory activity (Fig. 4).
3.2.2. Pyrimidinone analogs
With the exception of xanthine analogs as DPP-4 inhibitors, Xie
et al. [54] kept the scaffold of Alogliptin constant and replaced the
cyanobenzyl group with the butynyl group to immediately generate
a series of pyrimidinone analogs, among these compounds, 28
(0.4 nM), which interacted with Ser630 and Glu 205/206, showed
better efficacy in vitro and in vivo than Alogliptin. A series of highly
potent DPP-4 inhibitors were identified by hybrid compound
design based on linagliptin and alogliptin [55]. The most promising
compound 29 (0.31 nM) exhibited 8.5-fold and 2.5-fold more
potent activity than alogliptin (2.63 nM) and linagliptin (0.77 nM),
respectively. Apart from keeping hydrogen bonding interactions
with Glu205 and Glu206, and p-p stacks with Try547, X-ray crystal
structure determination showed that compound 29 probably had
additional p-p stacks with Trp629. Li et al. [56] presented a series of
triazole based uracil derivatives as novel DPP-4 inhibitors, Com-
pounds 30 (64.31 nM) showed good selectivity over DPP-8 and
DPP-9; In addition, it could significantly improve oral glucose
tolerance in ICR mice and dose-dependently reduced glucose levels
in type 2 diabetic C57BL/6 mice which suggested compound 30
150 N. Li et al. / European Journal of Medicinal Chemistry 151 (2018) 145e157

Fig. 5. Pyrimidinone analogs.

could be a promising DPP-4 inhibitor for future treatment of T2DM
(Fig. 5).
3.2.3. Phenethylamine and phenpropylamine derivatives
Series of Phenethylamine and Tetrahyddropyran-constrained
Phenethylamine derivatives also showed potent inhibitory activ-
ity of DPP-4. Compound 31 (28 ± 1 nM) demonstrated possessing
similar levels of DPP-4 inhibitory activity to sitagliptin [57]. Com-
pound 32 (14 nM) showed the best inhibitory activity against DPP-4
enzyme comparable with that of the reference drug, sitagliptin
(7.8 nM) [58].
A number of epoxyhexane constrained phenethylamine de-
rivatives also exhibited a significant DPP-4 inhibitory activity. As
reported by Biftu et al. [59], compound 33 (1.4 nM) exhibited
potent, selective, efficacious in the diabetes pharmacodynamic
model, and had an excellent pharmacokinetic profile. Similarly,
compound 34 (0.12 nM) demonstrated exquisite DPP-4 potency,
selectivity across all proteases, ion channels and cytochrome P450
genes tested [60]. Li et al. [61] have reported series of novel epox-
yhexane constrained phenethylamine derivatives as potent DPP-4
inhibitors which were rationally designed utilizing highly effi-
cient three-dimensional molecular similarity based scaffold
hopping as well as electrostatic complementary methods. Com-
pounds 35 (2.06 nM) and 36 (1.9 nM) were the most potent ones
with good pharmacokinetic profiles.
Apart from phenethylamine derivatives, phenpropylamine de-
rivatives also showed remarkable inhibition of DPP-4. Jadav et al.
[62] have reported a series of novel phenpropylamine derivatives as
potential DPP-4 inhibitors. Optimized analogue 37 (8.5 ± 0.4 nM)
showed superior DPP-4 inhibitory activity, compared to Sitagliptin
(18 ± 2.4 nM). The 3D binding modes of compound 37 to DPP-4
showed that aminomethyl group of piperidone ring was respon-
sible for H-bonding interaction with the side-chains of Glu205 and
Glu206 in S2 pocket and difluorophenyl ring occupyed S1 pocket.
Compound 38 (2.8 nM) and 39 (2.8 nM) also exhibited significant
inhibition of DPP-4 [63]. Other phenpropylamine derivatives also
showed potent DPP-4 inhibitory activities [64]. Of these tested
compounds, 40 was determined to be acceptable for advancement
to the clinic with a DPP-4 Ki of 0.9 nM and a DPP8/9 selectivity of
5400 and 3600, respectively (Fig. 6).
3.2.4. Arylmethylamine analogs
Maezaki et al. [65] discovered series of pyridinemethylamine
analogs with carboxylic acids incorporated in quinoline-based

Fig. 6. Phenethylamine and phenpropylamine derivatives.

 N. Li et al. / European Journal of Medicinal Chemistry 151 (2018) 145e157 151

Fig. 7. Arylmethylamine analogs.

templates as potential DPP-4 inhibitors. Among them, compound
41 (5.5 nM), 42 (2.6 nM), and 43 (7.2 nM) demonstrated sub-
nanomolar to nanomolar inhibition. In addition, Maezaki et al. [65]
reported series of quinolinemethylamine derivatives with carbox-
ylic acids incorporated in quinoline-based templates as potential
DPP-4 inhibitors. Among them, compound 44 (0.38 nM) showed
subnanomolar to nanomolar inhibition.
Quinazolinonemethylamine derivatives also exhibited marked
DPP-4 inhibitory activity [63]. In the investigated group of com-
pounds, 45 (4.8 nM) exhibited the most potent activity against DPP-
4.
Xiao et al. [66] designed and synthesized another series of novel
indolmethylamine compounds as potent inhibitors of DPP-4.
Compound 46 (232.8 nM) selectively inhibited the activity of
DPP-4 over DPP-9 (Fig. 7).
3.2.5. Other non-peptidomimetic DPP-4 inhibitors
New N3-benzylidene (substituted)-2-phenyl-N4-(thiazol-2-yl)-
quinazoline-3,4-(4H)-diamine derivatives were designed and syn-
thesized by Ali et al. [67]. Compound 47 (0.76 nM), 48 (1.33 nM), 49
(1.62 nM), 50 (1.22 nM) showed potent DPP-4 inhibitory activity;
among them, compound 47 exhibited most promising DPP-4
inhibitory activity and good antioxidant result. SAR studies of
compound 47 showed that several molecular interactions including
hydrogen bond, p-p interaction and hydrophobic interactions were
crucial for inhibitory activity. Moreover, amino group was also
necessary since hydrogen bond was observed with the carboxyl
group of Arg125 and Arg699 residue. Ali et al. [68] reported a novel
series of quinazoline derivatives as potent inhibitors of DPP-4,
compound 51 (1.12 nM) presented the most significant results
with good inhibition selectivity for DPP-4 over DPP-8/9. Molecular
docking studies suggested that hydrogen bond was observed be-
tween the nitrogen of the quinazoline ring and Tyr631. The hy-
droxyl group of compound 51 was very important for DPP-4
binding affinity since a salt bridge was formed between the hy-
droxyl group and Glu 206/205. Furthermore, other hydrogen bond
interactions with Arg125, Hie740 (tautomer of His740), Ser630, and
Trp629 were explained the enhanced binding affinity.
With the exception of quinazoline analogs, various triazolo [5,1-
c][1,2,4]triazine derivatives exhibited DPP-4 inhibitory activity. In
this novel series of DPP-4 inhibitors, compound 52 (28.05 mM)
exhibited the most potent activity against DPP-4 [69]. Wu et al. [70]
designed several series of heterocyclic compounds as initial targets.
Among them, compound 53 (1.7 nM) demonstrated robust glucose

Fig. 8. Quinazoline analogs and Other non-peptidomimetic DPP-4 inhibitors.

152 N. Li et al. / European Journal of Medicinal Chemistry 151 (2018) 145e157
Fig. 9. Terpenoids & steroids glycoside.
reduction efficacy after oral administration in mice, as well as po-
tential for a long duration of action (Fig. 8).
4. Natural DPP-4 inhibitors(2012e2017)
4.1. Terpenoids & steroids glycoside
The active ingredients of mycelium powders of nonotus obliquus
were responsible for the diabetes activity [71]. Molecular docking
between the compounds and DPP-4 revealed that compounds 54,
55, 56, 57, 58 might be the active components responsible for the
DPP-4 inhibitory activity. Ayachi et al. [72] studied the DPP-4
inhibitory activity of Rebaudioside A and Stevioside extracted
from the Stevia plant. By molecular modeling methods, Stevioside
59 presented a more optimized inhibition of DPP-4 (Fig. 9).
4.2. Flavonoids & phenols
Some phenolic compounds may show remarkable DPP-4
inhibitory activity. Fan et al. [73] investigated the DPP-4 inhibi-
tion of some phenolic compounds compared to diprotin A 60
(4.21 ± 2.01 mM), a reference standard inhibitory compound. Well-
characterized anthocyanins (ANC, 0.07 ± 0.02 to > 300 mM) from
berry wine blends showed good DPP-4 inhibitory effect in vitro and
in silico [73]. In addition, among the twenty-seven phenolics tested,
16 of which showed DPP-4 inhibitory activity, including luteolin 61
(0.12 ± 0.01 mM), apigenin 62 (0.14 ± 0.02 mM), quercetin 63
(2.92 ± 0.68 mM), flavone 64 (0.17 ± 0.01 mM), hesperetin 65
(0.28 ± 0.07 mM), naringenin 66 (0.24 ± 0.03 mM), kaempferol 67
(0.49 ± 0.02 mM), genistein 68 (0.48 ± 0.04 mM), resveratrol 69
(0.6 ± 0.4 nM), cyanidin 70 (1.41 ± 0.25 mM), caffeic acid 71
(3.37 ± 0.14 mM), malvidin 72 (1.41 ± 0.44 mM), eriocitrin 73
(10.36 ± 0.09 mM), cyanidin-3-glucoside 74 (0.42 ± 0.09 mM), epi-
gallocatechin gallate 75 (10.21 ± 0.75 mM), gallic acid 76
(4.65 ± 0.99 mM). Among these compounds, resveratrol 69
(0.6 ± 0.4 nM) showed the highest DPP-4 inhibitory effect in vitro
and in silico [73]. A naturally occurring compound naringin 77,
abundantly present in the peels of Orange, may physically bind
with DPP-4 enzyme and inhibit its action on GLP-1 degradation,
enhancing the insulin secretion and glucose disposal along with the
protective effects on the pancreatic islets [74]. Extracts from rose-
mary and Mexican oregano were identified significant inhibitory
activities of DPP-4. Biochemically, the best inhibitors of DPP-4 were
cirsimaritin 78 (0.43 ± 0.07 mM), hispidulin 79 (0.49 ± 0.06 mM), and
naringenin 80 (2.5 ± 0.29 mM) [75] (Fig. 10).
4.3. Polypeptides
Peptides released from dairy ingredients may have potent DPP-4
inhibitory activities. Peptides, isolated from tuna cooking juice and
hydrolyzed by Protease XXIII (PR) and orientase (OR), exhibited
significant DPP-4 inhibitory activity [76]. The amino acid sequences
of the three peptides isolated from PR and OR hydrolysates, Pro-
Gly-Val-Gly-Gly-Pro-Leu-Gly-Pro-Ile-Gly-Pro-Cys-Tyr-Glu 81
(1412.7 Da, 116.1 mM), Cys-Ala-Tyr-Gln-Trp-Gln-Arg-Pro-Val-Asp-
Arg-Ile-Arg 82 (1690.8 Da, 78.0 mM) and Pro-Ala-Cys-Gly-Gly-Phe-
Try-Ile-Ser-Gly-Arg-Pro-Gly 83 (1304.6 Da, 96.4 mM), showed the
dose dependent inhibition effect of DPP-4.
The rice bran peptides (2.3 ± 0.1 mg/mL) produced with Uma-
mizyme G, showed potent DPP-4 inhibitory activity; among tested
rice bran peptides, Ile-Pro 84 demonstrated the strongest DPP-4
inhibitory activity [77].
N. Li et al. / European Journal of Medicinal Chemistry 151 (2018) 145e157 153

Fig. 10. Flavonoids & phenols.

154 N. Li et al. / European Journal of Medicinal Chemistry 151 (2018) 145e157
The peptide sequences identified as Gly-Pro-Ala-Glu 85
(372.4 Da) and Gly-Pro-Gly-Ala 86 (300.4 Da)，which derived from
Atlantic salmon skin gelatin，showed potent DPP-4 inhibitory ac-
tivity [78].
Harnedy et al. [79] reported the DPP-4 inhibitory activities of
several peptide sequences, purified and identified from an aqueous
Palmaria palmata protein extract hydrolyzed with Corolase PP;
Following purification three novel DPP-4 inhibitory peptides with
IC50 values in the range 43e159 mM, Ile-Leu-Ala-Pro 87, Leu-Leu-
Ala-Pro 88 and Met-Ala-Gly-Val-Asp-His-Ile 89, exhibited potent
in vitro DPP-4 inhibitory activity.
Eight dipeptides were shown to inhibit DPP-4 and Val-Trp 90
(65.69 ± 2.95 mM) showed the most potent inhibitory activity to-
ward DPP-4; in addition, the most potent hydrolysate inhibitors of
milk protein hydrolysates were generated from casein and lacto-
ferrin [80]. In their other work, Nongonierma et al. [81] studied the
DPP-4 inhibitory activity of a whey protein hydrolysate
(1.34 ± 0.11 mg/mL) generated with a food-grade pancreatic
enzyme preparation; furthermore, simulated gastrointestinal
digestion of whey protein hydrolysate (1.02 ± 0.05 mg/mL) showed
an increased DPP-4 inhibitory potency.
5. The active site of DPP-4
The large cavity of DPP-4 (diameter  20 Å) formed between the
a/b-hydrolase domain and an eight-bladed b-propeller domain
made it possible to accept inhibitors of various shapes [82]. The
fully understanding of the interaction between DPP-4 enzyme and
the bioactive substances plays a significant role in designing novel
Fig. 11. The binding site of DPP-4. S2 pocket (Glu205 and Glu206, Ser209, Phe357, Arg358 and Arg125, green), S1 pocket and other residues (Ser630, Tyr631, Val656, Trp659, Tyr662,
Tyr666, Asn710, Val711 and His740, Val207, Lys544, Tyr547, Trp627, Trp629, Asp708, red). (For interpretation of the references to colour in this figure legend, the reader is referred to
the Web version of this article.)
DPP-4 inhibitors. Recently, the binding modes of DPP-4 inhibitors
were performed by molecular docking and/or pharmacophore
modeling. Nabeno et al. [83] reviewed the binding modes of
recently launched DPP-4 inhibitors in the active site. The reversed
binding of b-phenethylamine inhibitors of DPP-4 was presented by
Nordhoff et al. [84]. Patel et al. [85] and Li et al. [86] have reported
some of the active sites of DPP-4. By Reviewing literature it is
concluded that the binding pocket of DPP-4 involves S1 pocket
(formed by Ser630, Tyr631, Val656, Trp659, Tyr662, Tyr666,
Asn710, Val711 and His740), S2 pocket (containing the active triad
Glu205 and Glu206, Ser209, Phe357, Arg358 and Arg125), catalytic
triad Val207, Lys544, Tyr547, Trp627, Trp629, Asp708 and other
residues, of which S2 pocket is associated with selectivity of DPP-4
inhibitors (Fig. 11).
6. Conclusion and perspective
DPP-4 is a promising target for the treatment of T2DM. Since the
first peptidomimetic DPP-4 inhibitor sitagliptin became available in
2006, increasing DPP-4 inhibitors have been launched in the mar-
ket. So far, eight peptidomimetic DPP-4 inhibitors have been
entered the market; the other four inhibitors launched in the
market belong to non-peptidomimetic series.
This article reviewed fifty-three synthetic compounds respon-
sible for the DPP-4 inhibitory activity of which eight synthetic
compounds exhibited the potent DPP-4 inhibitory with the IC50
value below 1 nM (34, 29, 10, 44, 28, 19, 26 and 47). However,
compound 34 was not suitable to be further studied as a potential
once weekly inhibitor due to the discontented preclinical
 N. Li et al. / European Journal of Medicinal Chemistry 151 (2018) 145e157
Fig. 12. Key interactions and binding models of DPP-4 inhibitors.
pharmacokinetic profile. The others might be studied as candidates
of potential DPP-4 inhibitors. Apart from synthetic compounds,
twenty-seven natural compounds and peptides released from dairy
ingredients were also summarized for identifying potential DPP-4
inhibitors. Only compound 66 showed the strongest inhibitory
activity with the IC50 value below 1 nM. Their physico-chemical
properties, biological activities against DPP-4, selectivity against
DPP-8/9 and SAR were also discussed.
As a second line treatment, the safety of DPP-4 inhibitors has
been extensively studied in recent years. Although DPP-4 has many
substrates other than incretins, such as chemokines, cytokines,
neuropeptides, peptide YY1e36 and some growth factors [87], no
adverse effect relating to these substrates has been observed in
clinical trials [88]. No significant increased risk of total cardiovas-
cular diseases (CVDs) was found in the DPP-4 inhibitors versus
glimepiride group. In other words, DPP-4 inhibitors did not in-
crease cardiovascular risk compared with glimepiride regardless of
CVD history and diabetes duration [89]. In addition, due to the
glucose-dependency on the effects of GLP-1 the risk of hypogly-
cemia is very low during DPP-4 inhibition [90]. Compared with
GLP-1 analogs, DPP-4 inhibitors display body weight neutral, and
gliptins can be used alone or as add-ons to metformin sulphony-
lureas or thiazolidinediones [91]. Incidence of adverse effects such
as nausea, diarrhoea, and vomiting were lower with DPP-4 in-
hibitors than with metformin or GLP-1 agonists [92]. Similarly,
studies reported by Kamiya et al. [93] showed no significant dif-
ference of the incidence of severe adverse effects between DPP-4
inhibitors and placebo. However, due to serious methodological
problems and a small number of studies, a definitive conclusion has
yet to be drawn.
The SARs analyses of potent DPP-4 inhibitors indicate that pyr-
rolidine, aminopiperidine, xanthine, carbonyl, cyanobenzyl and
other groups are crucial for inhibitory activity. The aromatic ring
core (Such as pyrimidine, benzimidazole, quinoline, isoquinoline,
pyridine, benzene, etc) provides p-p interaction with Arg125. In
addition, the xanthine core forms hydrogen bonds with Tyr630 and
p-p interaction with Tyr547. Benzene ring, cyanobenzyl, butynyl, or
other small cyclic substituent is necessary since it occupies S1
pocket with hydrophobic interaction with Ser630/His740. In
particular, aminopiperidine or piperazine is crucial for DPP-4
inhibitory activity, which forms salt bridge with Glu205, Glu206
155
or Tyr662 in S2 pocket (Fig. 12). In summary, DPP-4 is a promising
target for the treatment of T2DM, this review might be useful for
molecular designing and will significantly promote the develop-
ment of potent DPP-4 inhibitors as T2DM drugs.
Abbreviations
CVDs, cardiovascular diseases; DPP-4, Dipeptidyl peptidase-4;
DPP-7, dipeptidyl peptidase-7; DPP-8, dipeptidyl peptidase-8;
DPP-9, dipeptidyl peptidase-9; DIO mice, diet-induced obesity
mice; FAP, Fibroblast Activation Protein; GIP, glucose-dependent
insulinotropic polypeptide; GLP-1, glucagon-like peptide-1;
GSPEs, grape seed-derived procyanidins; ICR mice, Institute of
Cancer Research mice; IDF, International Diabetes Federation;
OGTT, oral glucose tolerance test; PR, Protease XXIII; OR, orientase;
SARs, Structure-activity relationship; T2DM, type 2 diabetes
mellitus.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 81773586, 81703354), and Shandong
Provincial Natural Science Foundation for Distinguished Young
Scholars (JQ201722), and Key research and development project of
Shandong province (2016GSF201193, 2016ZDJS07A13,
2016GSF115002, 2016GSF115009), and Key Research Program of
Frontier Sciences, CAS (QYZDB-SSW-DQC014), and the Project of
Discovery, Evaluation and Transformation of Active Natural Com-
pounds, Strategic Biological Resources Service Network Program of
Chinese Academy of Sciences (ZSTH-026), and National Science
Foundation of China (NSFC)-Shandong Joint Fund (U1706213), and
National Program for Support of Top-notch Young Professionals,
and Taishan scholar Youth Project of Shandong province and
Qingdao Marine Biomedical Science and Technology Innovation
Center project (2017-CXZX01-1-1, 2017-CXZX01-3-9).
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.ejmech.2018.03.041.
156 N. Li et al. / European Journal of Medicinal Chemistry 151 (2018) 145e157

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