Structural optimization of pyrazolo[1,5-a]pyrimidine derivatives as potent and highly selective DPP-4 inhibitors

Article abstract of DOI:10.1016/j.ejmech.2020.112850

Our previous discovery of pyrazolo [1,5-a]pyrimidin-7(4H)-one scaffold-based DPP-4 inhibitors yielded two potent compounds b2 (IC₅₀ = 79 nM) and d1 (IC₅₀ = 49 nM) but characterized by cytotoxicity. Herein, with scaffold hopping and fragment-based drug design strategies, highly potent and selective pyrazolo [1,5-a]pyrimidine DPP-4 inhibitors were found featured by reduced or diminished cytotoxicity. Specifically, c24 (IC₅₀ = 2 nM) exhibits a 25 to 40-fold increase of inhibitory activity respect to those of b2 and d1, respectively, 2-fold from Alogliptin (IC₅₀ = 4 nM), and remarkable selectivity over DPP-8 and DPP-9 (>2000 fold). Further docking studies confirmed that the pyrazolo [1,5-a]pyrimidine core interacts with the S1 pocket whereas its substituted aromatic ring interacts with the sub-S1 pocket. The interactive mode in this case resembles that of Alogliptin and Trelagliptin. Further in vivo IPGTT assays in diabetic mice demonstrated that c24 effectively reduces glucose excursion by 48% at the dose of 10 mg/kg, suggesting that c24 is worthy of further development as a potent anti-diabetes agent.

Full text of DOI:10.1016/j.ejmech.2020.112850

European Journal of Medicinal Chemistry 208 (2020) 112850
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Structural optimization of pyrazolo[1,5-a]pyrimidine derivatives as
potent and highly selective DPP-4 inhibitors
,
b
,
,
Jian Shen a 1, Xinxian Deng a 1, Ran Sun a, Mojdeh S. Tavallaie a, Juntao Wang a,
Qingqing Cai c, Celine Lam a, Shuwen Lei a, Lei Fu a *, Faqin Jiang a
,
, **
a Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd. Minhang
District, Shanghai, 200240, PR China
b Viva Biotech Ltd. (Shanghai), No. 334 Aidisheng Rd., Pudong District, Shanghai, 201203, PR China
c Department of Pharmacy, Fudan University Affiliated Zhongshan Hospital, No. 250 Xiaomuqiao Rd. Shanghai, 200032, Xuhui District, Shanghai, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Our previous discovery of pyrazolo [1,5-a]pyrimidin-7(4H)-one scaffold-based DPP-4 inhibitors yielded
two potent compounds b2 (IC50 ¼ 79 nM) and d1 (IC50 ¼ 49 nM) but characterized by cytotoxicity.
Herein, with scaffold hopping and fragment-based drug design strategies, highly potent and selective
pyrazolo [1,5-a]pyrimidine DPP-4 inhibitors were found featured by reduced or diminished cytotoxicity.
Specifically, c24 (IC50 ¼ 2 nM) exhibits a 25 to 40-fold increase of inhibitory activity respect to those of b2
and d1, respectively, 2-fold from Alogliptin (IC50 ¼ 4 nM), and remarkable selectivity over DPP-8 and
DPP-9 (>2000 fold). Further docking studies confirmed that the pyrazolo [1,5-a]pyrimidine core interacts
with the S1 pocket whereas its substituted aromatic ring interacts with the sub-S1 pocket. The inter-
active mode in this case resembles that of Alogliptin and Trelagliptin. Further in vivo IPGTT assays in
diabetic mice demonstrated that c24 effectively reduces glucose excursion by 48% at the dose of 10 mg/
kg, suggesting that c24 is worthy of further development as a potent anti-diabetes agent.
© 2020 Elsevier Masson SAS. All rights reserved.
Received 21 June 2020
Received in revised form
16 August 2020
Accepted 13 September 2020
Available online 19 September 2020
Keywords:
Type 2 diabetes mellitus (T2DM)
DPP-4 inhibitor
Pyrazolo[1,5-a]pyrimidine derivatives
Fragment-based drug design
Scaffold hopping
1. Introduction
developed [3e6]. Nevertheless, despite their excellent regulation of
blood glucose level, respective inconvenient administration and
Diabetes is a fast-growing chronic metabolic disorder. To date,
415 million people worldwide live with diabetes, and the number is
expected to be 592 million by 2035. Type 2 diabetes mellitus
(T2DM) accounts for more than 90% of all diabetic patients [1]. The
complications of diabetes, such as coronary artery disease, hyper-
tension, retinopathy and stroke, severely affect patients’ quality of
life and increase the risk of death.
Traditionally, there are five categories of oral antidiabetic drugs,
biguanides, thiazolidinediones, sulfonylureas, meglitinides, and a-
glucosidase inhibitors. These drugs were reported to have adverse
events such as hypoglycemia, weight gain, gastrointestinal stress
and cancer risk [2]. Recently, three new categories, DPP-4 in-
hibitors, glucagon-like peptide-1 (GLP-1) receptor agonist and
side effects restrict their compliance in patients. For example, GLP-1
receptor agonists need by injection and induce gastrointestinal
stress [7], and SGLT2 inhibitors lower blood pressure and increase
genital infection [8].
Among all categories of antidiabetic drugs, DPP-4 inhibitors
have demonstrated their advantages in terms of mode-of-action,
good patient compliance and tolerance [4]. While DPP-4 in-
hibitors have drawn great attention, some side effects, such as the
elevated risk of cardiovascular death, heart failure, pancreatitis and
pancreatic cancer were reported [9,10]. New design and develop-
ment strategies were employed, resulting in Omarigliptin [11],
Trelagliptin [12] and compound 1 [4] with low cytotoxicity and
long-acting effect (Fig. 1).
sodium-glucose co-transporter
2
(SGLT2) inhibitors were
Our research on DPP-4 inhibitors began with full structural
analyses of DPP family binding sites and the preparation of two tool
compounds b2 and d1 (Fig. 2) [13], that are structurally analogs of
Alogliptin. While potent activities were achieved with b2
(IC50 ¼ 79 nM) [13] and d1 (IC50 ¼ 49 nM), in vitro cytotoxicity was
introduced as well.
* Corresponding author.
** Corresponding author.
E-mail addresses: leifu@sjtu.edu.cn (L. Fu), jfq2008@sjtu.edu.cn (F. Jiang).
Authors contributed equally.
1
https://doi.org/10.1016/j.ejmech.2020.112850
0223-5234/© 2020 Elsevier Masson SAS. All rights reserved.

J. Shen, X. Deng, R. Sun et al.
European Journal of Medicinal Chemistry 208 (2020) 112850
Fig. 1. Representative Potent DPP-4 inhibitors.
discovery strategies to design a series of new DPP-4 inhibitors.
These ligands’ structures featured in an amine stands at 50 position
and a substituted aromatic ring occupies 7’ position (Fig. 3). We
proposed that these novel chemical entities would remain the
typical binding mode to DPP-4 [14e18], and generate inhibitory
activity for DPP-4 and better selectivity over other DPP family
members such as DPP-8 and DPP-9.
2. Results and discussion
Fig. 2. Our Tool Compounds as DPP-4 inhibitors [13].
2.1. Chemistry
Further SAR studies on b2, d1, Trelagliptin and Alogliptin revealed
that (R)-piperidin-3-amine and substituted benzyl groups are key
components that impact DPP-4 inhibitory activity. Specifically, the
substituted benzyl group is supposed to stretch into the S1 pocket,
and (R)-piperidin-3-amine can bind with amino acid residues E205
and E206 (Fig. 3) [5]. Our preliminary results from these tool com-
pounds also suggested that re-orientation of the core structure sta-
bilizes ligand’s conformation and improves the activity [13].
The synthesis of the target compounds is depicted in Schemes 1
and 2. Specifically, 1 was obtained by condensation and cyclization
of 1H-pyrazol-5-amine and diethyl malonate. Chlorination of 1
with POCl3 using N, N0-dimethyl-aniline base yielded the key in-
termediate 2, which underwent condensation reactions with
respective anilines or amines at ambient temperature to offer 3.
Substitution of 3 with (R)-piperidin-3-yl carbamate yielded 4 fol-
lowed by deprotection giving c1-c14 as the final product. The c16 e
c25 was synthesized by substitution of 3 with piperazine. The c27
Herein we utilized the pyrazolo [1,5-a]pyrimidine core struc-
ture, and applied the scaffold hopping and fragment-based drug
Fig. 3. Design of pyrazolo [1,5-a]pyrimidine derivatives as novel DPP-4 inhibitors based on known DPP-4 inhibitors and our previous DPP-4 inhibitors.
2

J. Shen, X. Deng, R. Sun et al.
European Journal of Medicinal Chemistry 208 (2020) 112850
Scheme 1. i. n-Bu3N, 130 ꢀC; ii. POCl3, N,N0-dimethyl-aniline, 100 ꢀC; iii. TEA, i-PrOH or 60% NaH, DMF; iv. 1. N,N0-dimethyl-aniline, DMF, 90 ꢀC; v. TFA, DCM.
The SAR analysis revealed that in the hydrophobic region,
substituted aromatic rings such as aniline and benzylamine are very
important for the activity. Ligands with electron donating groups
(EDG) exhibit better activities than those with electron withdrawing
groups (EWG), such as c1 (1.2
mM) and c2 (9.1 mM) vs. c3 (25.3 mM),
c5 (22.2 M). The hydrogen on the amino group is pivotal for the
m
activity, because the introduction of methyl group on the amino
group of aniline resulted in a dramatic decrease of DPP-4 inhibitory
activity, e.g. c1 (1.2
mM) and c16 (0.8 mM) vs. c7 (>100 mM) and c21
(80 M). We proposed that the conformation restriction of the li-
m
gands is the reason why the N- methyl group leads to the decrease of
the DPP-4 inhibitory activity. Ligands with aromatic heterocycles as
substituted aminopyridines and 1H-pyrazol-3-amine exhibited
moderate activity, compared with aniline and benzylamine, such as
c13 (14.4 mM), c15 (31.8 mM) and c26 (>100 mM).
The amine region is fundamental for the potency. The ligands
with piperazine substitution exhibited better activity than those
Scheme 2. i. 130 ꢀC, neat; ii. POCl3, N,N0-dimethyl-aniline, 100 ꢀC; iii. N,N0-dimethyl-
aniline, DMF, 90 ꢀC; iv. TFA, DCM.
with (R)-piperidin-3-amine substitution, e.g. c16 (0.8
(1.2 M), c19 (0.4 M) vs. c4 (17.7 M), c17 (1.6 M) vs. c2 (9.1
The piperazine modification effectively boosted ligand activity up
to 40 times (c4:17.7 M vs. c19:0.4 M). The amine with a free NH is
critical to the activity, because the replacement of piperazine with
morpholine or tert-butylamine led to the loss of activity, such as
m
M) vs. c1
m
m
m
m
m
M).
was constructed by substitution of 2 with 2 equivalents of t-
butylamine.
m
m
Compounds c15 and c26 were synthesized via a slightly
different path, as shown in Scheme 2. 1H-pyrazol-5-amine and N,
N0-dimethylaniline were dissolved in diethyl malonate and heated
to 110 ꢀC overnight to yield the diamide 6. Treating 6 with POCl3 at
90 ꢀC for 3 h led to 7 by chlorination and cyclization process.
Subsequently, the substitution of 7 with (R)-piperidin-3-yl carba-
mate yielded 8.8 was treated with TFA in DCM gave c15. c26 was
synthesized by substitution of 7 with morpholine.
c26 (>100 mM) and c27 (>100 mM).
So far, the compounds exhibited excellent activity, but it is still
far from our expectations. Subsequently, we compared the struc-
tures of c1 and d1 and realized that what distinguishes them is the
position of substituent on the core structure and the distance be-
tween the aromatic group and core structure. We reasonably
assumed that prolonging the distance between the aromatic group
and the core structure with a linker may gain us more potent in-
hibitors. We designed and synthesized compounds c8-c11 bearing
a benzylamine group or phenylethylamine to test the hypothesis.
Indeed, the length of the linker between the core and the aromatic
ring holds a concrete and robust influence on inhibitory activity. For
instance, about 4e5 times enhanced activity was observed by
2.2. Bioassay and SAR analyses
The DPP-4 inhibitory activity of all compounds was examined on
a human DPP-4 enzyme derived from Caco-2 cells according to the
previously reported method [13]. The results are shown in Table 1.
To understand the structure-activity relationship (SAR), we
focused on 1) the hydrophobic region as aniline, benzylamine, aro-
matic heterocycles and tert-butylamine, 2) the amine region as (R)-
piperidin-3-amine, tert-butylamine, piperazine and morpholine and
3) the linker between the hydrophobic region and core region.
adding just one atom to the linker, such as c5 (22.2
(5.7 M) vs. c11 (1.1 M).
mM) vs. c10
m
m
Thus far, we can draw out that the nature of the amine and the
linker are key factors to enhance the inhibitory activity. So, we
3

J. Shen, X. Deng, R. Sun et al.
European Journal of Medicinal Chemistry 208 (2020) 112850
Table 1
DPP-4 inhibitory activity (IC50) of the pyrazolo [1,5-a]pyrimidine derivatives (c series).
No.
Structures
DPP-4 IC50
1.2 0.5
(mM)
A
R
c1
A1
c2
c3
c4
A1
A1
A1
9.1 0.5
25.3 3.5
17.7 2.4
c5
c6
c7
A1
A1
A1
22.2 3.1
11.7 3.4
>100
c8
c9
A1
A1
0.3 0.1
7.9 0.3
c10
c11
A1
A1
5.7 1.1
1.1 0.2
c12
c13
A1
A1
8.1 1.1
14.4 3.2
4

J. Shen, X. Deng, R. Sun et al.
European Journal of Medicinal Chemistry 208 (2020) 112850
Table 1 (continued)
No.
Structures
DPP-4 IC50
2.4 0.4
(mM)
A
R
c14
c15
A1
A1
31.8 1.3
c16
c17
c18
c19
A2
A2
A2
A2
0.8 0.3
1.6 0.1
23.6 1.3
0.4 0.2
c20
A2
3.5 0.1
c21
c22
A2
A2
80.5 4.4
0.47 0.2
c23
c24
A2
A2
0.09 0.01
0.002 0.001
c25
c26
A2
A3
2.8 0.5
>100
c27
t-BuNH
>100
Alogliptin
0.004 0.001
Data are represented as mean SD (n ¼ 3).
5

J. Shen, X. Deng, R. Sun et al.
European Journal of Medicinal Chemistry 208 (2020) 112850
Fig. 4. Linker extension and piperazine modification strategy.
Fig. 5. A. B. Superimpose of Compound c24 and Alogliptin and Trelagliptin in the active site of DPP-4. Compound c24 is colored in cyan, Alogliptin is colored in violet and Tre-
lagliptin is colored in yellow; DPP-4 is colored in white and shown as cartoon and surface. (For interpretation of the references to color in this figure legend, the reader is referred to
the Web version of this article.)
presume to design new compounds applying this new strategy, as
shown in Fig. 4. The compounds with piperazine as amino and
phenylethylamine as the aromatic ring should produce efficient
nearly 250-fold higher inhibitory activity than compound c5
(22.2 M) (Table 3).
Based on our SAR findings and design strategy which are sum-
marized as piperazine modification and linker extension, rede-
m
inhibitory activity. This guided us to create c23 (0.09
mM), which
comprised of piperazine and 2, 4-Cl phenylethylamine, and showed
signing of compound c4 (17.7
mM) that possess (R)-piperidin-3-
6

J. Shen, X. Deng, R. Sun et al.
European Journal of Medicinal Chemistry 208 (2020) 112850
Table 2
Selectivity assays of the selected compounds.
No.
DPP-4 (
m
M)
DPP-8 (
m
M)
DPP-8/DPP-4
DPP-9 (
m
M)
DPP-9/DPP-4
c1
c2
c3
c8
1.2
9.1
25.3
0.3
7.9
>100
>100
>100
>100
>50
>100
>10
>4
>1000
>6
>100
>100
>100
>100
>50
>100
>10
>4
>1000
>6
c9
c10
c11
c12
c14
c17
c19
c20
c22
c23
c24
c25
alogliptin
5.7
1.1
8.1
2.4
1.6
0.4
3.5
0.47
0.089
0.002
2.8
>100
>100
>100
>50
>100
>100
>100
>100
>100
>50
>17
>100
>12
>20
>60
>200
>30
>200
>1000
>2000
>35
>100
>100
>100
>50
>100
>100
>100
>100
>100
>50
>17
>100
>12
>20
>60
>200
>30
>200
>1000
>2000
>35
>100
>50
>100
>50
0.004
>2000
>2000
Table 3
IPGTT assays of compound c24 in diabetic C57BL/6 mice.
Blood glucose (mM)
0 h
AUC
0.5 h
1 h
1.5 h
2 h
Diabetes control
c24 intraperitoneal
1 mg/kg
5 mg/kg
10 mg/kg
15.6 2.4
33.6 2.3
25.0 1.2
23.9 2.9
23.9 0.7
51.2 3.9
12.7 0.7
13.4 1.1
12.3 0.3
25.7 1.9
23.4 4.4
16.2 1.2
18.6 2.6
18.5 1.9
14.4 0.1
17.9 2.8
17.4 3.7
13.0 1.6
14.8 1.0
15.1 1.0
10.9 1.5
38.0 4.0
36.7 5.8
27.1 1.9
c24 oral
10 mg/kg
Alogliptin
10 mg/kg
15.8 4.5
15.3 2.3
26.7 4.5
22.9 3.7
19.1 3.3
17.4 3.7
18.5 3.3
16.3 2.1
15.6 3.1
15.0 5.6
40.0 4.1
45.9 3.8
Data are represented as mean SD (n ¼ 4).
amine and 2,4-difluoroaniline as substitutions brought us to com-
pound c24 (Fig. 4). The later has a piperazine substitution at 50
position and a 2,4-difluorobenzoylamine at 7’ position. It has an
explicit superior potency by 14,000-fold increase, presenting IC50 of
2 nM, 2-fold higher than Alogliptin.
compound for the extensive in vivo bioassays in mice to test its
potential to treat type 2 diabetes.
2.3. Molecular docking analysis
Subsequently, compounds with IC50 value less than 10 mM were
The binding of c24 in the DPP-4 active site generates a similar
binding mode to those of Alogliptin and Trelagliptin (Fig. 5). The di-
fluorobenzyl group occupies S1 pocket comprised of S630, Y662
and H740. Furthermore, the piperazine forms H-bond interaction
with E205. The pyrazolo [1,5-a]pyrimidine core locates at the
selected to perform the selectivity assay over DPP-8 and DPP-9
(Table 2). Data and results showed that the tested compounds
showed excellent selectivity over the DPP-4 homologues proteins.
Compound c24 selectivity is heightened by 2000 times compared
to Alogliptin over DPP-8 and DPP-9. Therefore, we selected this
center of the active site where a
p-p interaction with Y547 is
formed to stabilize the binding conformation. Such binding
conformation sheds light on the molecular mechanism of the
potent inhibitory activity of c24.
2.4. Cytotoxicity bioassay
Previous studies clarified that pyrazolo [1,5-a]pyrimidin analogs
could be developed as anti-cancer agents [19,20]. Consequently, we
investigated the cytotoxicity of our synthetic ligands in order to
recognize the compounds’ safety. Cellular growth and viability of
compounds c8, c22, c23 and c24 were performed on HepG2 cells
using MTT assay. HepG2 cells were incubated with the inhibitors at
varying concentrations for 48 h. As illustrated in Fig. 6, c8, c22 and
c23 displayed a dose-dependent manner on cell viability. Inter-
estingly, Compound c24, which is the most potent ligand in our
study, presents very low cytotoxicity at concentrations ranging
from 1 mM to 100 mM. Even when the dose raised to 100 mM, c24
exhibits more than 90% cell viability, which suggests c24 is a potent
and safe ligand for further in vivo anti-hyperglycemic assays.
Fig. 6. Cytotoxicity effect of compounds c8, c22, c23 and c24 on HepG2 cells after 48 h
is evaluated by MTT assay. Each value was presented as mean SD, n ¼ 3.
7

J. Shen, X. Deng, R. Sun et al.
European Journal of Medicinal Chemistry 208 (2020) 112850
Fig. 7. A. Effects of compound c24 in various concentrations and 10 mg/kg Alogliptin on glucose levels after IPGTT or OGTT in diabetic male C57BL/6 mice. B. The glucose AUC
(diabetes C57BL/6 mice) was determined from 0 to 120 min. Percent reduction values for each treatment were generated from the AUC data normalized to the saline-challenged
controls. Data are represented as mean SD (n ¼ 4), *P < 0.05 versus negative control for 2 h, **P < 0.01 versus negative control for 2 h, one-way ANOVA followed by LSD post-test.
2.5. Glucose tolerance test (IPGTT and OGTT)
decreased the blood glucose levels compared to the diabetic control
group on the 14th day of treatment (46% reduction) while Alog-
liptin managed to lower the blood glucose by 57% compared with
the control group. During the starting 5 days, the decrease of blood
glucose is not significant in either the c24 group or Alogliptin, then
the gradual decline was observed.
The in vivo anti-hyperglycemia effects of compound c24 were
evaluated by performing intraperitoneal glucose tolerance test
(IPGTT) in high-fat diet-fed/streptozotocin (HFD/STZ) induced
T2DM male C57BL/6 mice following our previously reported
method [13]. A single dose of compound c24 administered to male
C57BL/6 mice 30 min prior to an IPGTT reduced plasma glucose
excursion in a dose-dependent manner from 1 mg/kg to 10 mg/kg.
Alogliptin was used as a positive control. The results are shown in
Table 3 and Fig. 7. Compound c24 reduced the area under the curve
from 0 to 120 min (AUC)0-120 min to 43% in diabetic C57BL/6 mice,
which transcended the effect of Alogliptin (30% reduction, Fig. 6) at
the same dose. We also performed OGTT with 10 mg/kg c24 to
evaluate the oral effectiveness of the ligand in reducing blood
glucose. Oral administration of c24 induced an AUC reduction of
22% which indicated a significant blood glucose lowering effect.
3. Conclusion
In conclusion, we have designed, synthesized, and evaluated a
series of novel pyrazolo [1,5-a]pyrimidine derivatives as potent and
selective DPP-4 inhibitors which had a similar binding mode as
Alogliptin to DPP-4. Compound c24 demonstrates excellent in vitro
DPP-4 inhibitory activity with IC50 of 2 nM, high selectivity over
DPP-8 and DPP-9 and low cytotoxicity profile. Compound c24 also
possessed good in vivo efficacy in IPGTTs in healthy and diabetic
mice, and demonstrated its capability to be a potential antidiabetic
agent.
2.6. Anti-hyperglycemic bioassays in HFD/STZ induced T2DM mice
Declaration of competing interest
Based on the DPP-4 inhibitory activities and selectivity, com-
pound c24 was selected for the chronic effects experiment. The
chronic effects of compound c24 were investigated in HFD/STZ
induced type 2 diabetic male C57BL/6 mice with a single dose
(10 mg/kg/day) for 14 days, with Alogliptin as a positive control.
The results are depicted in Fig. 8. Compound c24 significantly
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgments
The authors would like to express their appreciation to the
Medicine and Engineering Interdisciplinary Research Fund of
Shanghai Jiao Tong University (YG2015QN03, YG2014MS10 and
YG2017MS77), National Natural Science Foundation of China
(81202397) and Shanghai Natural Science Fund (12ZR1415400) for
the funding and budgeting supports. We thank Professor Yongxiang
Wang’s team (Shanghai Jiao Tong University) for their excellent
assistance and cooperation in the biological studies of this research.
We also thank Shuhua for careful proofreading and editing of this
manuscript.
Appendix A. Supplementary data
Fig. 8. Effects of compound c24 (10 mg/kg, single dose) in plasma glucose levels in
chronically treating HFD/STZ mice for 14 days. Data are presented as means SD of 4
mice. *P < 0.05 versus diabetic control for 14 days, **P < 0.01 versus diabetic control
for 14 days, one-way ANOVA followed by LSD post-test.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.ejmech.2020.112850.
8

J. Shen, X. Deng, R. Sun et al.
European Journal of Medicinal Chemistry 208 (2020) 112850
[12] N. Inagaki, H. Onouchi, H. Sano, N. Funao, S. Kuroda, K. Kaku, SYR-472, a novel
once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor, in type 2 diabetes
mellitus: a phase 2, randomised, double-blind, placebo-controlled trial, Lancet
Diabetes Endocrinol. 2 (2014) 125e132.
[13] X. Deng, J. Shen, H. Zhu, J. Xiao, R. Sun, F. Xie, C. Lam, J. Wang, Y. Qiao,
M.S. Tavallaie, Y. Hu, Y. Du, J. Li, L. Fu, F. Jiang, Surrogating and redirection of
pyrazolo[1,5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective
DPP-4 inhibitors, Bioorg. Med. Chem. 26 (2018) 903e912.
[14] H. Xie, L. Zeng, S. Zeng, X. Lu, X. Zhao, G. Zhang, Z. Tu, H. Xu, L. Yang, X. Zhang,
S. Wang, W. Hu, Highly potent dipeptidyl peptidase IV inhibitors derived from
Alogliptin through pharmacophore hybridization and lead optimization, Eur.
J. Med. Chem. 68 (2013) 312e320.
[15] Q. Li, L. Han, B. Zhang, J. Zhou, H. Zhang, Synthesis and biological evaluation of
triazole based uracil derivatives as novel DPP-4 inhibitors, Org. Biomol. Chem.
14 (2016) 9598e9611.
References
[1] S. Chatterjee, K. Khunti, M.J. Davies, Type 2 diabetes, Lancet 389 (2017)
2239e2251.
[2] B. Ahren, DPP-4 inhibitors, Best Pract. Res. Clin. Endocrinol. Metabol. 21 (2007)
517e533.
[3] S. Li, H. Xu, S. Cui, F. Wu, Y. Zhang, M. Su, Y. Gong, S. Qiu, Q. Jiao, C. Qin, J. Shan,
M. Zhang, J. Wang, Q. Yin, M. Xu, X. Liu, R. Wang, L. Zhu, J. Li, Y. Xu, H. Jiang,
Z. Zhao, J. Li, H. Li, Discovery and rational design of natural-product-derived 2-
Phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine analogs as novel and
potent dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2
diabetes, J. Med. Chem. 59 (2016) 6772e6790.
[4] S. Li, C. Qin, S. Cui, H. Xu, F. Wu, J. Wang, M. Su, X. Fang, D. Li, Q. Jiao, M. Zhang,
C. Xia, L. Zhu, R. Wang, J. Li, H. Jiang, Z. Zhao, J. Li, H. Li, Discovery of a natural-
product-derived preclinical candidate for once-weekly treatment of type 2
diabetes, J. Med. Chem. 62 (2019) 2348e2361.
[16] C. Shu, H. Ge, M. Song, J.H. Chen, H. Zhou, Q. Qi, F. Wang, X. Ma, X. Yang,
G. Zhang, Y. Ding, D. Zhou, P. Peng, C.K. Shih, J. Xu, F. Wu, Discovery of imi-
gliptin, a novel selective DPP-4 inhibitor for the treatment of type 2 diabetes,
ACS Med. Chem. Lett. 5 (2014) 921e926.
[5] X. Deng, M.S. Tavallaie, R. Sun, J. Wang, Q. Cai, J. Shen, S. Lei, L. Fu, F. Jiang, Drug
discovery approaches targeting the incretin pathway, Bioorg. Chem. 99 (2020)
103810.
[17] Y. Ikuma, H. Hochigai, H. Kimura, N. Nunami, T. Kobayashi, K. Uchiyama,
T. Umezome, Y. Sakurai, N. Sawada, J. Tadano, E. Sugaru, M. Ono, Y. Hirose,
H. Nakahira, Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent
and selective dipeptidyl peptidase IV (DPP-4) inhibitors: use of a carboxylate
prodrug to improve bioavailability, Bioorg. Med. Chem. 23 (2015) 779e790.
[18] W.L. Wu, J. Hao, M. Domalski, D.A. Burnett, D. Pissarnitski, Z. Zhao,
A. Stamford, G. Scapin, Y.D. Gao, A. Soriano, T.M. Kelly, Z. Yao, M.A. Powles,
S. Chen, H. Mei, J. Hwa, Discovery of novel tricyclic heterocycles as potent and
selective DPP-4 inhibitors for the treatment of type 2 diabetes, ACS Med.
Chem. Lett. 7 (2016) 498e501.
[19] Y. Deng, B. Sun, G. Shipps, R. Matthew, Z. Meng, W. Windsor, H. Zeng, B. Long,
L. Xiao, Discovery of pyrazolo 1,5-a pyrimidin-7-amine derivatives as mTOR
kinase domain inhibitors: hit to lead optimization, Abstr. Pap. Am. Chem. Soc.
248 (2014).
[20] G. Brenchley, J. Charrier, C. Davis, S. Durrant, G.E.I. Jardi, D. Fraysse, J. Jimenez,
D. Kay, R. Knegtel, F. Pierard, J. Pinder, D. Shaw, P. Storck, J. Studley, H. Twin,
I.J.G. Etxebarria, New pyrazolo(1,5-a)pyrimidin-2-ylamine derivatives useful
for treating cancer e.g. mouth cancer, sarcoma, lung cancer, gastrointestinal
cancer, liver cancer, Nervous System Cancer, Breast Cancer and Medullary
Thyroid Carcinoma, WO2014143241-A1; US2014275009-A1; US8957078-B2;
US2015291601-A1; EP2970289-A1; JP2016512239-W,
[6] Sodium glucose cotransporter-2 (SGLT-2) inhibitors, in: LiverTox: Clinical and
Research Information on Drug-Induced Liver Injury, National Institute of
Diabetes and Digestive and Kidney Diseases, Bethesda (MD), 2012.
[7] J.Y. Cheang, P.M. Moyle, Glucagon-like peptide-1 (GLP-1)-Based therapeutics:
current status and future opportunities beyond Type2 diabetes, Chem-
MedChem 13 (2018) 662e671.
[8] R. Puckrin, M.P. Saltiel, P. Reynier, L. Azoulay, O.H.Y. Yu, K.B. Filion, SGLT-2
inhibitors and the risk of infections: a systematic review and meta-analysis of
randomized controlled trials, Acta Diabetol. 55 (2018) 503e514.
[9] E. Bonora, M. Cigolini, DPP-4 inhibitors and cardiovascular disease in type 2
diabetes mellitus. Expectations, observations and perspectives, Nutr. Metabol.
Cardiovasc. Dis. 26 (2016) 273e284.
[10] N. Mikhail, Safety of dipeptidyl peptidase 4 inhibitors for treatment of type 2
diabetes, Curr. Drug Saf. 6 (2011) 304e309.
[11] T. Biftu, X. Qian, P. Chen, D. Feng, G. Scapin, Y.D. Gao, J. Cox, R.S. Roy,
G. Eiermann, H. He, K. Lyons, G. Salituro, S. Patel, A. Petrov, F. Xu, S.S. Xu,
B. Zhang, C. Caldwell, J.K. Wu, K. Lyons, A.E. Weber, Novel tetrahydropyran
analogs as dipeptidyl peptidase IV inhibitors: profile of clinical candidate
(2R,3S,5R)-2- (2,5-difluorophenyl)-5-(4,6-dihydropyrrolo [3,4-c]pyrazol-5-
(1H)-yl)tetrahydro-2H-pyran-3-amine (23) [corrected], Bioorg. Med. Chem.
Lett 23 (2013) 5361e5366.
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