Design and biological evaluation of tetrahydropyridine derivatives as novel human GPR119 agonists

Article abstract of DOI:10.1016/j.bmcl.2019.126855

A series of novel tetrahydropyridine derivatives were prepared and evaluated using cell-based measurements. Systematic optimization of general structure G-1 led to the identification of compound 35 (EC₅₀ = 4.9 nM) and 37 (EC₅₀ = 8.8 nM) with high GPR119 agonism activity and moderate clog P. Through single and long-term pharmacodynamic experiments, we found that compound 35 showed a hypoglycemic effect and may have an effect on improving basal metabolic rate in DIO mice. Both in vitro and in vivo tests indicated that compound 35 was a potential potent GPR119 agonist in allusion to T2DM treatment.

Full text of DOI:10.1016/j.bmcl.2019.126855

Journal Pre-proofs
Design and biological evaluation of tetrahydropyridine derivatives as novel hu-
man GPR119 agonists
Zeping Zuo, Miaomiao Chen, Xiaoni Shao, Xinying Qian, Xiaocong Liu, Xia
Zhou, Jiawei Xiang, Pengchi Deng, Yan Li, Hui Jie, Chunqi Liu, Xiaobo Cen,
Yongmei Xie, Yinglan Zhao
PII:
S0960-894X(19)30829-7
DOI:
https://doi.org/10.1016/j.bmcl.2019.126855
BMCL 126855
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
21 October 2019
21 November 2019
22 November 2019
Please cite this article as: Zuo, Z., Chen, M., Shao, X., Qian, X., Liu, X., Zhou, X., Xiang, J., Deng, P., Li, Y., Jie,
H., Liu, C., Cen, X., Xie, Y., Zhao, Y., Design and biological evaluation of tetrahydropyridine derivatives as novel
human GPR119 agonists, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.
2
019.126855
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Design and biological evaluation of tetrahydropyridine derivatives as novel human
GPR119 agonists
a,
a,
a
a
a
a
Zeping Zuo *, Miaomiao Chen *, Xiaoni Shao , Xinying Qian , Xiaocong Liu , Xia Zhou ,
a
b
a
a
a
c
a, ‡
Jiawei Xiang , Pengchi Deng , Yan Li , Hui Jie , Chunqi Liu , Xiaobo Cen , Yongmei Xie
and Yinglan Zhao a, ‡
a
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan
University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
b
Analytical &Testing Center, Sichuan University, Chengdu 610041, China
c
National Chengdu Center for Safety Evaluation of Drugs, State Key Lab of Biotherapy, West
China Hospital, Sichuan University, Chengdu 610041, China
*These authors contributed equally to this work.
‡
Correspondence to: Yinglan Zhao and Yongmei Xie, State Key Laboratory of Biotherapy
and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation
rd
Center for Biotherapy, 17#, 3 Section, Renmin South Road, Chengdu 610041, China.
E-mail: zhaoyinglan@scu.edu.cn; xieym@scu.edu.cn
Abstract
A series of novel tetrahydropyridine derivatives were prepared and evaluated using
cell-based measurements. Systematic optimization of general structure G-1 led to the
identification of compound 35 (EC = 4.9 nM) and 37 (EC = 8.8 nM) with high GPR119
5
0
50
agonism activity and moderate clogP. Through single and long-term pharmacodynamic
experiments ,we found that compound 35 showed a hypoglycemic effect and may have an
effect on improving basal metabolic rate in DIO mice. Both in vitro and in vivo tests indicated
that compound 35 was a potential potent GPR119 agonist in allusion to T2DM treatment.
Keywords: type 2 diabetes; GPR119 agonist; 1, 2, 3, 6-tetrahydropyridine derivatives; OGTT
1

Type 2 diabetes mellitus (T2DM) results when increases in beta cell function and/or mass
1
cannot compensate for rising insulin resistance. According to the International Diabetes
Federation, 387 million people were affected by diabetes in 2014. The prevalence of the
2
disease is expected to rise to 592 million by 2035. Although a variety of treatment options
have been developed in past decades, many patients still suffered from hypoglycemia, weight
gain, cardiovascular risks and strokes. To avoid such pitfalls and to improve glycemic control
with minimum side effects, new medications that increase insulin secretion in a
glucose-dependent manner could be potential.3
GPR119 is a member of rhodopsin δ-group G protein-coupled receptors expressed
predominantly in the pancreatic islet β-cells and incretin-releasing intestinal cells in the
digestive tract. Agonists of GPR119 receptor cause an increase in intracellular cAMP levels
via Gαs coupling to adenylate cyclase both in a pancreatic β-cell line and in transfected
cells.4-6 Additionally, the activation of GPR119 leads to glucose-dependent insulin secretion
along with insulinotropic peptide (GIP) and glucose-independent glucagon-like peptide 1
7
(
GLP-1) release. These studies suggested that GPR119 would be an attractive target for the
treatment of type 2 diabetes and may be more amenable to the discovery of orally active small
molecule agonists.
8
Since the first potent GPR119 agonists with disclosed structure AR231453 published in
2
008, several groups have reported the discovery of a number of different series of GPR119
agonists9-13, and some drug candidates have progressed to clinical trials (Figure 1). APD668 14
and subsequently APD597 15 in clinical trials did observe positive effects on meal-associated
glucose excursions, however, they apparently did not obtain meaningful improvements of
glucose tolerance in type 2 diabetic patients.16 Similar results were reported by
GlaxoSmithKline from their internal GPR119 program at the American Diabetes Association
th
meeting in 2011. Moreover, Astellas announced on November 15 2012 that it received a
notice from AstraZeneca not to exercise an exclusive option to acquire the Phase Ⅱ clinical
asset PSN821 for the treatment of type 2 diabetes.17
2

N
O
O
N
NO2
N
H
N
S
O
N
O
S
N
N
F
O
AR231453
O
N
N
O
O
N
O
N
N
F
O
GSK1292263
N
S
O
N
N
O
S
N
O
N
N
N
N
APD668
O
O
N
N
H
N
N
O
S
O
N
N
N
N
MBX-2982
APD597
O
O
Figure 1. Structures of five selected synthetic GPR119 agonists
However, clinical tests of MBX-2982, a potential first-in-class GPR119 agonist, are still
underway. Preclinical data indicate that MBX-2982 is a potent selective orally-active GPR119
agonist functions through agonist that functions through a dual mechanism. It directly induces
insulin secretion through actions on β cells in islet and stimulates release of GLP-1 from the
gut which indirectly increases insulin secretion, both of which offer improved glucose
homeostasis over existing diabetes therapy strategies, with potential for weight loss and
1
8
improved islet health. MBX-2982 has completed four Phase I studies and PhaseⅡ study. In
all studies to date, MBX-2982 demonstrated dose-dependent increases in drug exposure with a
profile supporting once daily oral dosing that was safe and well tolerated with no serious
adverse events, adverse event trends or dose-limiting toxicities.
Since the crystal structure of GPR119 has not been determined, ligand-based drug design
was used to fit the typical molecular architecture of GPR119 agonists. In an effort to discover
novel GPR119 agonist with high potency against T2DM. We recently performed a rational
drug design in which scaffold hopping was applied on MBX-2982 (see Figure 2). MBX-2982
was selected as a lead structure and repalced piperidine to tetrahydropyridine, therefore, we
hopped the 2-(piperidinyl)thiazole structure motif to 2-(tetrahydropyridinyl)thiazole structure
(G-1).
In this investigation, we performed structural modifications to motif G-1. A series of
1
9
2
-(tetrahydropyridin-4-yl)thiazole derivatives were synthesized, and the structure-activity
3

relationship (SAR) of this series of compounds is discussed. For compound 35, GPR119
agonism activity, oral glucose tolerance test and long-term pharmacodynamic evaluation
experiment in DIO mice were evaluated.
X R1
S
O
N
N
S
N
N
N
Scaffold Hopping
N
N
N
N
R4
N
X= O or NH
MBX-2982
G-1
Figure 2. Structures of MBX-2982 and Designed Structure
1
4
The subsequent structural optimization was focused on the R and R regions of G-1 . In
4
1
the first step, we fixed R as the tert-butyl carbonate and varied the R group substituents. The
synthetic routes are outlined in Scheme 1. Briefly, protection of commercially available
piperidine-4-carboxamide
with
(Boc) O
gave
intermediate
tert-butyl
2
4
4
4
-carbamoylpiperidine-1-carboxylate 1, which was vulcanized to yield to tert-butyl
-carbamothioylpiperidine-1-carboxylate
2.
Tert-butyl
-(4-(chloromethyl)thiazol-2-yl)piperidine-1-carboxylate 3 was prepared by direct cyclization
1,3-dichloroacetone. Bromination of afforded the tert-butyl
-bromo-4-(4-(chloromethyl)thiazol-2-yl)piperidine-1-carboxylate 4. Elimination coupling of
yielded key intermediates 5 . A nucleophilic substitution reaction between 5 and various
using
3
4
4
2
0
substituted amines or phenols yielded intermediates 7-28.
Compound 23-26 were
deprotected by trifluoroacetic acid to produce intermediates 29-32. Coupling of 29-32 with
-chloro-5-ethylprimidine or 2-chloro-5-ethyl-pyridine through a nucleophilic reaction
provided 33-40.21, 22
2
4

S
Cl
O
NH2
O
S
a
b
c
N
HN
Boc
N
Boc N
NH2
NH2
N
Boc
1
2
3
Boc
S
Cl
d
N
S
Cl
Br
N
N
e
N
Boc
N
Cl
S
N
Boc
N
3
Boc
4
5
N
g
R1
X
S
2
R -X
NH2
f
7-28
2
N
R -X = 6a-f, or substituted phenyl or
heterocycle
H N
N
X=O or NH
2
H N
N
2
N
6
a
X=O or NH
NH2
R3
f
HO
N
N
HO
R3
N
N
6b-f
Scheme 1. Reagents and conditions: (a) (Boc) O, DMAP, DCM, rt, 2h, 95%; (b) Lawesson’ s
2
reagent, DCM, dimethoxyethane, rt, 1.5h, 60%-65%; (c) 1, 3-dichloroacetone, MgCO3,
MgSO , acetone, reflux, 4h, 90%-95%; (d) N-bromosuccinimide, AIBN, CCl , reflux, 1h,
4
4
1
8%; (e) K CO , acetonitrile, reflux, overnight, 30%-32%; (f) NaN , Trimethoxymethane,
2 3 3
AcOH, reflux, 80%-90%. (g) Mono- or di- substituted phenyl or heterocycle, Cs CO , KI,
2
3
acetonitrile, reflux, 30%-62%.
R4
H
Boc
N
N
N
N
N
N
h
i
R1
1
1
R O
S
R O
S
O
S
23-26
29-32
33-40
Scheme
2.
(h)
20
%
TFA,
DCM,
rt,
0.5h;
(i)
2
9
-chloro-5-ethylprimidine/2-chloro-5-ethyl-pyridine, K CO / DIPEA, isopropanol /DMF,
2 3
0 ℃, 2-4 h, 20%-40%.
We assessed the stimulatory activities of these compounds on GPR119 receptor with
1
8
cAMP HTRF method. Oleoylethanolamide (OEA) was used as a reference agonist. We first
investigated the GPR119 agonist activities of twenty-two tetrahydropyridine compounds with
1
diverse R substitutions of cyclohexylbenzene, phenyl, thiophene, benzo-dioxole and biaryl
structures and X of O or NH (Scheme 1). Here, a typical GPR119 agonists, MBX-2982, was
5

used as a positive control. Thus, in our medicinal chemistry campaign for finding novel
GPR119 agonists, we hope to modulate compounds’ clogP values while maintaining their
GPR119 agonistic effects. Among these final molecules, compound 26 with a
1
2
-chloro-4-(1H-tetrazol-1-yl)phenyl at the R position was the potent for GPR119 agonist
(
EC : 107 nM), and it possessed an higher clogP value than MBX-2982 . Compounds 24 and
50
2
5 showed a similar enzyme agonist (EC : 113 and 108 nM), but had a higher clogP value
50
than MBX-2982. Another compound 23 with a 4-(methylsulfonyl)phenyl-group at the R1
position of tetrahydropyridine scaffold had an even lower clogP value than MBX-2982 but
exhibited a decreased EC value toward the GPR119 (678 nM). Other compounds in this
5
0
series did not show over 50% agonistic activity at our maximum test concentration (10 μM).
Compound 23 and 24 Maximum percentage efficacy showed much stronger activity than 21
and 22. The difference between these are X of O or NH. These demonstrate O substitution is
better for enzyme agonistic activity over NH substitution. The following structural
optimization will be based on compounds 23, 24, 25 and 26 since these demonstrated the most
potent agonist of GPR119 activity compared to MBX-2982.
Table 1 GPR119 agonist activity of tert-butyl carbamates at concentration of 10 μM
R1
S
X
N
N
Boc
Compd
7
R1
X
clogP a
% Max Eff. b
EC50（nM）
O
6.83
19.67
nd
O
O
8
9
O
4.24
3.85
11.47
13.00
nd
nd
O
S
O
NH
Cl
I
1
1
0
1
NH
O
5.70
5.25
nd
nd
Cl
5.05
-7.34
6

CF3
1
1
2
3
NH
O
6.30
5.40
-2.16
7.04
nd
nd
CF3
F3C
O
O
1
1
1
4
5
6
O
O
O
4.87
3.62
5.00
-14.25
-5.65
nd
nd
nd
Br
O
O
O
62.54
O
1
1
7
8
NH
O
3.91
3.93
-6.25
10.66
nd
nd
O
O
O
O
O
1
9
NH
3.24
-7.44
nd
2
2
2
2
2
0
1
2
3
4
O
NH
NH
O
7.11
2.41
3.28
2.98
3.60
1.70
26.03
35.46
77.99
95.44
nd
nd
O
S
O
N
N
N
N
nd
O
S
678
113
O
N
N
N
N
O
N
N
N
N
2
2
5
6
F
O
O
3.58
4.12
104.55
94.42
108
107
N
N
N
N
Cl
N
N
N
2
2
7
8
N
O
O
3.60
3.13
-2.17
8.40
nd
nd
N
O
N
N
N
7

MBX-2982
OEA
3
6
.13
.57
113.00
100.00
3.9
930
a
Octanol-water partition coefficient (logP) was calculated by ChemBioDraw Ultra 14.0.
Maximum percentage efficacy compared with reference agonist oleoylethanolamide (OEA).
b
Data are shown as mean.
nd, not determined.
Table 2 GPR119 agonist activity of Boc replacement at concentration of 10 μM
O R1
S
N
N
R4
Compd
R1
R4
clogP a
% Max Eff. b
EC50（nM）
O
S
N
3
3
3
3
3
3
3
4
3
4
5
6
7
8
9
0
2.41
105.30
70.5
O
N
O
S
3.18
3.03
3.79
3.01
3.77
3.54
71.50
110.30
78.50
Nd
4.9
Nd
8.8
Nd
10.2
Nd
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
F
F
N
N
115.30
89.57
N
N
N
N
N
N
N
N
N
N
Cl
Cl
N
109.30
72.71
N
N
N
N
4.31
3.13
N
N
N
MBX-2982
110.00
100.00
3.9
OEA
6
.57
930
a
Octanol-water partition coefficient (logP) was calculated by ChemBioDraw Ultra 14.0.
Maximum percentage efficacy compared with reference agonist oleoylethanolamide (OEA).
b
Data are shown as mean.
nd, not determined.
Next, we synthesized eight analogues of compounds 23, 24, 25 and 26 by introducing
8

4
2
-chloro-5-ethyl-primidine or 2-chloro-5-ethyl-pyridine groups at R to further enhance the
enzyme activity. As shown in Table 2, fifty percent of the synthesized analogues (33, 35, 37
and 39) reached nanomolar EC values . Compound 35 (IC : 70.5 nM) showed much lower
5
0
50
activity than 35 (IC : 4.9 nM), 37 (IC : 8.8 nM) and 39 (IC : 10.2 nM). It is not difficult to
5
0
50
50
find that a 4-(1H-tetrazol-1-yl)phenyl is favored for enzyme agonistic activity over
-(methylsulfonyl)phenyl substitution. Other four compounds (34, 36, 38 and 40) displayed
4
lower agonistic effects with Maximum percentage efficacy. We can find that
chloro-5-ethyl-primidine is better than 2-chloro-5-ethyl-pyridine for GPR119 agonistic
activity. Half of these newly synthesized molecules displayed good biological activity, over to
lead compounds 23, 24, 25 and 26. 33, 35, 37 and 39 described herein have improved EC50
values, Only 35 and 37 have lower clogP.
The compounds whose GPR119 receptor stimulatory effect over 50% at 10 μM in this
study were compound 17, 23, 24, 25, 26 and 33-40. Then, compound 35, 37 and 39 were
selected for further investigation. Acute pharmacological efficacy of these compounds was
2
3
tested by oral glucose tolerance test (OGTT). After administration of glucose, the plasma
concentration of glucose up to two hours was measured. The area under the curve (AUC) of
glucose decreased by 35.05%, 26.81%, 12.11% and 29.22%, at 100 mg/kg dose of 35, 37, 39
and MBX-2982 in normal mice, respectively. (Figure 3A and 3B). Then, compound 35, 37
and MBX-2982
demonstrates a dose-dependent effect from 0 to 120ꢀmin by 20.11% to
2
6.77%, 1.2% to 14.16% , and 18.47% to 26.72% at the dose of 20ꢀmg/kg and 50ꢀmg/kg,
respectively. (Figure 3C). Therefore, these results suggest that 35 showed a hypoglycemic
effect.
We tried to elucidate the physiological effect of repeated treatment of 35 in DIO mice for
4
4
weeks. Fasting glucose was expressively reduced at 20 mg/kg dose of 35 at 28 days (Figure
A). The AUC0–120 min values were significantly reduced in DIO mice fed 20 mg/kg of 35
compared to vehicle at 28 days after repetition treatment of it (Figure 4B and 4C),
compound 35 and MBX-2982 demonstrates glucose decrease from by 34.80% vs 23.61%.
Furthermore, food intake of the compound 35 treatment group was increased with the vehicle
group and MBX-2982 treatment group. However, body weight gain was potentially controlled
in a dose at a dose of 20 mg/kg for 4 weeks (Figure 4D and 4E). Therefore Compound 35 may
9

have an effect on improving basal metabolic rate in DIO mice. On the contrary, MBX-2982
(
20 mg/kg), just showed moderate effects in the same model. Although, MBX-2982 (EC =
50
3
.9 nM ) had more the agonistic effect than 35 (EC = 4.9 nM ). However, compound 35 had
50
better clogP (3.03 vs 3.13), was potent soluble in aqueous solutions than MBX-2982 (0.056 vs
.035 mg/ml) and had a better performance in membrane permeability (QPPCaco-2 and
0
QPPMDCK), which were predicted by ChemBioDraw, ALOGPS 2.1 and
Schrodinger_Suites_2016-1, respectively. Thence, compound 35 displayded a better in vivo
effect.
Figure 3. Effect of compound 35, 37 and 39 on oral glucose tolerance test in male C57BL/6
mice. (A) OGTT(2 g/kg/10 ml glucose) in C57BL/6J male mice treated with vehicle,
MBX-2982, 35, 37 and 39 (100 mg/kg). (B) The of blood glucose levels of MBX-2982, 35, 37
and 39 during an OGTT. (C) The AUC0-120min of blood glucose levels of MBX-2982, 35 and
3
7 at 20 mg/kg, 50 mg/kg and 100 mg/kg. Data are presented mean ± SD (n=6). **p <0.01,
**p＜0.001,****p＜0.0001 versus vehicle group.
*
1
0

Figure 4. Effect of compound 35 on blood glucose and food intake in DIO mice. (A) Fasting
glucose level at 28 days of compound 35 administration. (B) OGTT (2 g/kg glucose) in DIO
mice treated with vehicle, MBX-2982 and compound 35. (C) The AUC0-120min of blood
glucose levels of MBX-2982 and compound 35 at 20 mg/kg. (D) Average food intake after
compound 35 treatment. (E) Body weight was measured until 28 days. Data are presented
mean ± SD (n=6). **p <0.01, ***p＜0.001,****p＜0.0001 versus vehicle group.
Table 3. Solubility, Caco and MDCK Data
compound
logS a
Solubility (mg/ml)a
QPPCaco b
QPPMDCK b
MBX-2982
-4.10
-3.90
0.037
0.056
529.45
561.45
401.67
443.21
3
5
a
clogP calculated using ALOGPS 2.1.
b
Measured using Schrodinger_Suites_2016-1.
In conclusion, we have described the design, synthesis and preliminary biological
evaluation of novel 1, 2, 3, 6-tetrahydropyridine derivatives as potent GPR119 agonists. Our
work focused on the obtainment of candidate GPR119 agonists with stimulatory activity
towards GPR119 receptor, that is, compound 35 and compound 37. Though, in vitro,
MBX-2982 (EC = 3.9 nM ) showed stronger bioactivity in enzymatic level than compound
5
0
1
1

3
5 (EC = 4.9 nM). However, in vivo, tests indicated that compound 35 could better induce
50
GPR119 receptor activation and improve glucose excursions compared with MBX-2982.
Through a 100 mg/kg dose test of 35 and MBX-2982 in normal mice, these demonstrates
glucose decrease from by 35.05% vs 29.22%. Next, compound 35 and MBX-2982
demonstrates glucose decrease from by 34.80% vs 23.61% in the DIO mice. compound 35
showed a hypoglycemic effect and may have an effect on improving basal metabolic rate in
DIO mice. Although, MBX-2982 (EC = 3.9 nM) had more the agonistic effect than 35 (EC
5
0
50
=
4.9 nM), however, compound 35 had better physical and chemical properties (clogP = 3.03),
better soluble (0.056 mg/ml) and better performance in membrane permeability. These results
offered a very promising prospect for the treatment of type 2 diabetes mellitus, which could be
also attributed to its more suitable structure motif 2-(tetrahydropyridinyl)thiazole. Normally,
GPR119 agonist shows body-weight reduction based on the secretion of GLP-1 in animal
models. This phenomenon that compound 35 showed food intake was gained and body-weight
reduction compared with vehicle was interesting. Afterwards, long-term pharmacodynamic
evaluation experiment were evaluated again, whether food intake of the compound 35
treatment group increased. Further research on the detection of pharmacokinetic properties,
effect of chronic treatment with compound 35 in diabetic db/db mice and the mechanism of
compound 35 leading to increased intake are in progress, will be reported in due course.
Acknowledgments
This work was supported by National S&T Major project (2018ZX09201018), Project of the
National keypoint research and invention program of China Ministry of Science and
Technology (MOST-2016YFC1303200) and National Natural Science Foundation of China
(81773198).
References and notes
1
2
. Satin LS, Butler PC, Sherman AS, et al. Mol. Aspects. Med. 2015; 42: 61;
. International Diabetes Federation website:
http://www.idf.org/worlddiabetesday/toolkit/gp/facts-figures (retrieved on 24; 05: 2015;)
. George RE, Joseph S. Saudi. Pharm. J. 2014; 22: 403;
3
1
2

4
5
6
. Chu ZL, Jones RM, He H, et al. Endocrinology. 2007; 148: 2601;
. Soga T, Ohishi T, Matsui T, et al. Biochem. Biophys. Res. Commu. 2005; 326: 744;
. SakamotoY, Inoue H, Kawakami S, et al. Biochem. Biophys. Res. Commun. 2006; 351:
4
74;
7
8
. Lan H, Lin HV, Wang CF, et al. Br. J. Pharmacol. 2012; 165: 2799;
. Semple G, Fioravanti B, Pereira G, et al. J. Med. Chem. 2008; 51: 5172;
Jones RM, Leonard JN, Buzard DJ, et al. Expert Opin Ther Pat. 2009; 19: 1339;
0. Ritter K, Buning C, Halland N, et al. J. Med. Chem. 2015; 59: 3579;
9
.
1
1
1
1
1
1
1
1
1. Semple G, Ren A, Fioravanti B, et al. Bioorg. Med. Chem. Lett. 2011; 21: 3134;
2. McClure KF, Darout E, Guimarães CRW, et al. J. Med. Chem. 2011; 54: 1948;
3. Darout E, Robinson RP, McClure KF, et al. J. Med. Chem. 2013; 56: 301;
4. Semple G, Ren A, Fioravanti B, et al. Bioorg. Med. Chem. Lett. 2011; 21: 3134;
5. Semple G, Lehmann J, Wong A, et al. Bioorg. Med. Chem. Lett. 2012; 22: 1750;
6. Katz LB, Gambale JJ, Rothenberg PL, et al. Clin. Pharmacol. Ther. 2011; 90: 685;
7. Astellas received the Notice from AstraZeneca Not to Exercise the Option to Acquire
Diabetes Assets from Prosidion, a Subsidary of Astellas.
http://www.astellas.com/en/corporate/news/detail/astellas-received-the-notice-f.html.
(retrieved on 24; 05: 2015;)
1
8. CymaBay Pipeline: Potential Oral Incretin/Islet Therapy.
http://www.cymabay.com/pipeline_mbx2982.html (retrieved on 24; 05: 2015;)
9. Chen X, Ma JY, Song JG, Nashashibi I. WO Patent 2011153435 A1.
0. Bruhn JA, Pasteris RJ. WO Patent 2008091594 A2.
1
2
2
1. Chen, X.; Cheng, P.; Clemens, L. E.; Johnson, J. D.; Ma. J. Y.; Murphy, A.; Nashashibi, I.;
Rabbat, C. J.; Song, J.G.; Wilson, M. E.; Zhu, Y.; Zhao, Z. C. WO Patent 2008083238
A2.
2
2
2. Mcwherter, C. A.; Martin, R. L.; Karpf, D. B.; Roberts, B. K.; Lorenz, D. A.; Ketner, R. J.
WO Patent 2011163090 A1.
3. Ha TY, Kim YS, Kim C H, et al. Arch. Pharm. Res. 2014; 37: 671;
1
3

1
4