Design, synthesis, and biological evaluation of aryl N-methoxyamide derivatives as GPR119 agonists

Article abstract of DOI:10.1016/j.bmcl.2017.06.032

A series of N-methoxyamide derivatives was identified and evaluated as GPR119 agonists. Several N-methoxyamides with thienopyrimidine and pyridine scaffolds showed potent GPR119 agonistic activities. Among them, compound 9c displayed good in vitro activity and potency. Moreover, compound 9c lowered glucose excursion in mice in an oral glucose tolerance test and increased GLP-1 secretion in intestinal cells.

Full text of DOI:10.1016/j.bmcl.2017.06.032

Accepted Manuscript
Design, synthesis, and biological evaluation of aryl N-methoxyamide deriva-
tives as GPR119 agonists
Yoon Kyung Jang, Kyu Myung Lee, Kwan-Young Jung, Seung Kyu Kang,
Suvarna H. Pagire, Jun Mi Lee, Haushabhau S. Pagire, Kwang Rok Kim, Myung
Ae Bae, Hohjai Lee, Sang Dal Rhee, Jin Hee Ahn
PII:
S0960-894X(17)30635-2
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.06.032
BMCL 25066
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 March 2017
9 June 2017
12 June 2017
Please cite this article as: Jang, Y.K., Lee, K.M., Jung, K-Y., Kang, S.K., Pagire, S.H., Lee, J.M., Pagire, H.S., Kim,
K.R., Bae, M.A., Lee, H., Rhee, S.D., Ahn, J.H., Design, synthesis, and biological evaluation of aryl N-
methoxyamide derivatives as GPR119 agonists, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://
dx.doi.org/10.1016/j.bmcl.2017.06.032
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
Design, synthesis, and biological evaluation of aryl N-methoxyamide derivatives
as GPR119 agonists
Yoon Kyung Janga,†, Kyu Myung Leea,†, Kwan-Young Junga, Seung Kyu Kanga, Suvarna H. Pagirea, Jun Mi Leea,
Haushabhau S. Pagirea, Kwang Rok Kima, Myung Ae Baea, Hohjai Leeb,*, Sang Dal Rheea, Jin Hee Ahna,b,*
aDrug Discovery Division, Korea research Institute of Chemical Technology, Daejeon, 305-600, Republic of Korea
bDepartment of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
A series of N-methoxyamide derivatives was identified and evaluated as GPR119 agonists.
Several N-methoxyamides with thienopyrimidine and pyridine scaffolds showed potent GPR119
agonistic activities. Among them, compound 9c displayed good in vitro activity and potency.
Moreover, compound 9c lowered glucose excursion in mice in an oral glucose tolerance test and
increased GLP-1 secretion in intestinal cells.
Revised
Accepted
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Diabetes
N-methoxyamide derivative
GPR119
Treatment
The prevalence of type 2 diabetes mellitus (T2DM; non-
insulin dependent diabetes) is increasing worldwide in all age
groups. In order to deal with this situation several T2DM drugs
have been developed in past few decades, which are included but
not limited to, biguanides, sulfonylureas, thiazolidinediones,
meglitinides, glucagon-like peptide 1 (GLP-1) analogs, DPP-4
inhibitors, and SGLT-2 inhibitors.1-5 One of current focuses on
diabetes drug discovery is to identify new agents that protect and
preserve pancreatic β-cells.6 G protein-coupled receptor 119
(GPR119) is activated by endogenous ligand, which in turn,
induces glucose-stimulated insulin secretion (GSIS) in pancreatic
beta cells and GLP-1 in intestine. 7 GLP-1 has β-cell protection
and preservation potential through accumulating intracellular c
AMP and enhancing adenylate cyclase activation. Moreover, it
also has the ability to improve glucose homeostasis while
concurrently slowing gastric emptying by reducing the food
intake and promoting weight loss. 8-10 All of these characteristics
make GPR119 a promising target for the treatment of T2DM.
According to recent studies, many GPR119 agonists have
been reported,7 and few GPR119 agonists have been entered into
clinical trials but none have been approved up to date. In our
recent work, we have also identified a series of thienopyrimidine
derivatives.10 Most GPR119 agonists display structural
similarities, featuring a polar moiety (head group) such as
methylsulfonyl or tetrazole groups10-17 (Fig. 1).
Figure 1. Structures of GPR119 agonists: our previous compound (I) and
clinical agonists with disclosed structure (II) GSK1292263, (III) APD668,
(IV) APD597, (V) BMS-903452, and (VI) MBX-2982

With the goal of identifying a novel chemotype, we replaced
the polar head (methylsulfonyl or tetrazole) with diverse
functional groups and identified N-alkoxyamide moiety as a
methylsulfonyl or tetrazole surrogate. Thus, we report the
synthesis and biological evaluation of new N-alkoxyamide
GPR119 agonists.
The general synthetic procedure is outlined in Scheme 1.
Commercially available 4-bromobenzoyl chloride 1 was coupled
with N,O-dimethylhydroxylamine to yield 2, which was
borylated by cross-coupling with bis(pinacolato)diboron to
pinacol ester 3. Borylated compound 3 was coupled with
thienopyrimidine 10 or pyridine derivative 11 to obtain products
4 and 7. Boc groups of compounds 4 and 7 were deprotected by 4
M HCl to yield 5 and 8, which were further substituted with 5-
ethylpyrimidyl or isopropyl carboxylate moieties to obtain 6 and
9.
The synthesized N-methoxyamide derivatives were evaluated
for in vitro as GPR119 agonists (Tables 1-3) whereas
GSK1292263 (II in Fig. 1) was used as the reference standard.
To identify novel sulfone or tetrazole surrogates, diverse
functional groups including amide, N-sulfonyl amide, hydrazide,
N-methoxy-N-methylamide, N-methoxyamide, N-ethoxyamide,
N-benzyloxyamide, and 1,2-oxazinane were introduced on
thienopyrimidine and pyridine backbones.
Thienopyrimidine (10) and pyridine (11) moieties are known
linker groups in structures of GPR119 agonists.10,11 Introduction
of N-methoxy-N-methylamide as the polar head resulted in
compound 4a, showing potency (% activation relative to
GSK1292263 (100%) at 1 µM) comparable to the reference
compound (105 % activation at 1 µM) and good agonistic
activity (EC50 98 nM) (Table 1). In addition, compound 6b
showed moderate potency and good agonistic activity (EC50 156
nM). These results indicated that N-methoxyamide could be a
suitable methylsulfonyl/tetrazole surrogate. Next, N-methoxy-N-
methylamide group was replaced with N-methoxyamide (4b), N-
ethoxyamide (4c), N-benzyloxy amide (4e and 6c-d) and 1,2-
oxazinane (4d); however, these various derivatives showed
reduced potency compared to compound 4a.
Scheme 1. Reagents and conditions: (a) TEA, hydroxylamine, CH2Cl2
(>90%); (b) Bis(pinacolato)diboron, PdCl2 (dppf) complex with CH2Cl2,
potassium acetate, 1,4-dioxane, 80 °C (>90%); (c) PdCl2 (dppf) complex with
CH2Cl2, 3M Na2CO3, toluene, ethanol, reflux (68%); (d) 4M HCl in 1,4-
dioxane; (e) 1) pyrimidine, 2-chloro-5-ethylpyrimidine, K2CO3, acetonitrile,
90 °C (>70%); 2) carbamate, isopropyl chloroformate, K2CO3, CH2Cl2, 45 °C
(>70%).
Table 1. GPR119 agonist activity of aryl N-alkoxyamide derivatives with thienopyrimidine scaffolds
% Activation
at 1 µMa
Human GPR119
EC50 (nM)
Compound
Structure
4a
105
80
98
KRI-62008
6a
6b
4b
NDb
156
NDb
82
82

S
H
N
N
O
4c
73
66
NDb
NDb
N
N
N
O
O
O
4d
4e
6c
6d
81
41
53
83
NDb
NDb
a Activation relative to GSK1292263.
b Not determined.
Table 2. GPR119 agonist activity of aryl N-alkoxyamide derivatives with pyridine scaffolds
% Activation
at 1 µMa
Human GPR119
EC50 (nM)
Compound
Structure
106
171
7a
95
80
69
73
319
155
NDb
321
9a
9b
7b
7c
a Activation relative to GSK1292263.
b Not determined.
Table 3. GPR119 agonist activity of aryl N-alkoxyamide derivatives with thienopyrimidine and pyridine scaffolds
% Activation
at 1 µMa
Human GPR119
EC50 (nM)
Compound
Structure

4a
4f
105
87
98
53
81
NDb
6e
6f
90
67
100
82
64
4g
6g
4h
6h
199
57
88
100
105
114
100
73
77
7d
9c
96
92
9d
a Activation relative to GSK1292263.
b Not determined.
Based on data shown in Table 1, thienopyrimidine scaffold
was replaced with pyridine (11), and the activity data
summarized in Table 2. As shown in Table 2, most of the
pyridine compounds showed similar potency and activity to
thienopyrimidine analogs. Compounds 7a, 9a, and 9b showed
good to moderate potency and moderate agonistic activity (EC50
150-350 nM). Meanwhile, compounds 7b and 7c substituted with
benzyloxyamide and 1,2-oxazinane showed reduced potency,
similar to their thienopyrimidine analogs.
Table 1, 2. Therefore, herein supposed to need to modify other
parts by fixing N-methoxy-N-methylamide part. As shown in
Table 3, 2-fluoro aryl substituents increased the agonistic activity
of thienopyrimidine compounds. Compounds 4f, and 6f showed
good in vitro activities with an EC50 of 53 and 67 nM, compared
to 4a, and 6b. Compounds 4g, 4h, 6g, and 6h in which
methylamino group of the thienopyrimidine scaffold was
replaced with oxygen showed moderately improved potency and
agonistic activity compared to methylamine analogs 4a, 6a, 4f,
and 6e. Additionally, pyridine compounds 7d, 9c, and 9d showed
potential for further evaluation with significantly improved
We considered that N-methoxy-N-methylamide was the most
appropriate functional group from the activity data as shown in

agonistic activity (up to 5-fold) and potency relative to
compounds 7a, 9a, and 9b which lack of fluorine.
In conclusion, we identified N-methoxy-N-methylamide as a
novel methanesulfonyl/tetrazole surrogate in structures of
GPR119 agonists. Several compounds showed good agonistic
activity (EC50 < 100 nM) and potency. Among them, compound
9c showed good in vitro activity, in vivo efficacy (OGTT) as well
as GLP-1 secretion in intestinal cells.
From in vitro data, we chose four representative compounds
(6f, 6h, 9c and 9d) and performed in vivo oral glucose tolerance
tests (OGTT) (data not shown). Among them, compound 9c
showed good glucose lowering efficacy, therefore it was selected
as a prototype compound. As shown in Fig 2, compound 9c
significantly reduced plasma glucose levels (determined using
AUC) in OGTT at doses of 30 and 50 mg/kg.
Acknowledgments
This research was supported by a Korea Health Technology
R&D Project grant through the Korea Health Industry
Development Institute (KHIDI), funded by the Ministry of
Health & Welfare (A111345).
† These authors contributed equally to this work.
References and notes
1. Ahrén, B. Nat Rev Drug Discov 2009, 8, 369.
2. Inzucchi, S. E. J. Am. Med. Assoc. 2002, 287, 360.
3. Owens, D. R.; Zinman, B.; Bolli G. B. Lancet 2001, 358, 739.
4. Bailey, C. J. Curr. Diabet. Rep. 2005, 5, 353.
5. Campbell, R. K.; White, J. R. Diabet Educator, 2008, 34, 518.
6. Vetere, A.; Choudhary, A.; Burns, S. M.; Wagner, B.K. Nat Rev
Drug Discov 2014, 13, 278.
7. Ritter, K.; Buning, C.; Halland, N.; Pöverlein, C.; Schwink, L. J.
Med. Chem. 2016, 59, 3579.
8. (a) Jones, R. M.; Leonard, J. N.; Buzard, D. J.; Lehmann, J. Expert
Opin. Ther. Pat. 2009, 19, 1339; (b) Fyfe, M. C. T.; McCormack,
J. G.; Overton, H. A.; Procter, M. J.; Reynet, C. Expert Opin.
Drug Discov 2008, 3, 403; (c) Kang, S. U. Drug Discovery Today
2013, 18, 1309.
9. Overton, H. A.; Babbs, A. J.; Doel, S. M.; Fyfe, M. C.; Gardner, L.
S.; Griffin, G.; Jackson, H. C.; Procter, M. J.; Rasamison, C. M.;
Tang-Christensen, M.; Widdowson, P. S.; Williams, G. M.;
Reynet, C. Cell Metab. 2006, 3, 167.
10. Jeon, M. K.; Lee, K. M.; Kim, I. H.; Jang, Y. K.; Kang, S. K.;
Jeong, K. Y.; Kumar, J. A.; Rhee, S. D.; Jung, W. H.; Bae M. A.;
Kim, K. R.; Ahn, J. H. Bioorg. Med. Chem. Lett. 2014, 24, 4281.
11. Polli, J. W.; Hussey, E.; Bush, M.; Generaux, G.; Smith, G.;
Collins, D.; McMullen, S.; Turner, N.; Nunez, D. J. Xenobiotica
2013, 43, 498.
12. Nunez, D. J.; Bush, M. A.; Collins, D.; McMullen, S. L.; Gillmor,
D.; Apseloff, G.; Atiee, G.; Corsino, L.; Morrow, L.; Feldman, P.
L. PLoS One 2014, 9, e92494.
Figure 2. In vivo oral glucose tolerance tests of compound 9c
in normal mice. Data are expressed as means ± SEM for n = 7
mice/group. *P < 0.05, **P < 0.01
13. Semple, G.; Ren, A.; Fioravanti, B.; Pereira, G.; Calderon, I.;
Choi, K.; Xiong, Y.; Shin, Y.-J.; Gharbaoui, T.; Sage, C. R.;
Morgan, M.; Xing, C.; Chu, Z.-L.; Leonard, J. N.; Grottick, A. J.;
Al-Shamma, H.; Liang, Y.; Demarest, K. T.; Jones, R. M. Bioorg.
Med. Chem. Lett. 2011, 21, 3134.
14. Semple, G.; Lehmann, J.; Wong, A.; Ren, A.; Bruce, M.; Shin, Y.-
J.; Sage, C. R.; Morgan, M.; Chen, W.-C.; Sebring, K.; Chu, Z.-L.;
Leonard, J. N.; Al-Shamma, H.; Grottick, A. J.; Du, F.; Liang, Y.;
Demarest, K.; Jones, R. M. Bioorg. Med. Chem. Lett. 2012, 22,
1750
Differentiated NCI-H716 cells, which express high levels of
GLP-1 represent a useful cellular model for regulation of GLP-1
secretion in humans.19 Compound 9c (at 100 nM) significantly
stimulated GLP-1 secretion in NCI-H716 cells.
15. Wacker, D. A.; Wang, Y.; Broekema, M.; Rossi, K.; O’Connor,
S.; Hong, Z.; Wu, G.; Malmstrom, S. E.; Hung, C.-P.; LaMarre, L.;
Chimalakonda, A.; Zhang, L.; Xin, L.; Cai, H.; Chu, C.; Boehm,
S.; Zalaznick, J.; Ponticiello, R.; Sereda, L.; Han, S.-P.; Zebo, R.;
Zinker, B.; Luk, C. E.; Wong, R.; Everlof, G.; Li, Y.-X.; Wu, C.
K.; Lee, M.; Griffen, S.; Miller, K. J.; Krupinski, J.; Robl, J. A. J.
Med. Chem. 2014, 57, 7499.
16. Kang, S.-U. Drug Discovery Today 2013, 18, 1309.
17. Jones, R. M.; Leonard, J. N.; Buzard, D. J.; Lehmann, J. Expert
Opin. Ther. Pat. 2009, 19, 1339
18. Fang, J.; Tang, J.; Carpenter, A. J.; Peckham, G.; Conlee, C. R.;
Du, K. S.; Katamreddy, S. R. WO 2008/070692 A2, 2008.
19. Reimer, R. A.; Darimont, C.; Gremlich, S.; Nicolas-Metral, V.;
Ruegg, U. T.; Mace, K. Endocrinology 2001, 142, 4522.
Supplementary Material
Figure 3. Effects of compound 9c on GLP-1 release in NCI-
H716 cells. **P < 0.01
Supplementary data associated with this article can be found,
in the online version at doi:

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Design, synthesis and biological evaluation of
aryl N-methoxyamide derivatives as GPR119
agonists.
Leave this area blank for abstract info.
Yoon Kyung Jang, Kyu Myung Lee, Kwan-Young Jung, Seung Kyu Kang, Suvarna H. Pagire, Haushabhau S.
Pagire, Jun Mi Lee, Kwang Rok Kim, Myung Ae Bae, Hohjai Lee, Sang Dal Rhee, Jin Hee Ahn