In summary, we conducted optimization of the lead compound
4 and obtained 26 as a drug candidate of a GPR119 agonist for
further evaluations. We noticed the pivotal role of the fluorine
atom in 2-fluoro-4-(methylsulfonyl)aniline at the head moiety of
4, based on the analysis that the intramolecular hydrogen bond
between the fluorine atom and the aniline hydrogen was associat-
ed with the restriction of conformation, and found 5-
(methylsulfonyl)indoline as an optimal unit for the moiety. We
considered that planarity of the head moiety, involving not only
the conformational restriction but also less steric bulkiness
around the annulated part of the moiety, was a crucial structural
requirement for a potent GPR119 agonist. The optimized com-
pound 26 showed potent GPR119 agonistic activity (EC50 = 42
nM, Emax = 117%) with improved liver microsome clearance, and
exerted 33% reduction in blood glucose AUC at a dose of 10
mg/kg in an oral glucose tolerance test in C57BL/6N mice. Fol-
low-up studies and their results will be reported in due course.
hGPR119 agonistic activities
X
Y
EC50 (nM)
79
Emax (%)
S
NH
NMe
O
C
C
C
N
82
9
>1000
>1000
353
3
137
14. Semple, G.; Fioravanti, B.; Pereira, G.; Calderon, I.; Uy, J.; Choi,
K.; Xiong, Y.; Ren, A.; Morgan, M.; Dave, V.; Thomsen, W.;
Unett, D. J.; Xing, C.; Bossie, S.; Carroll, C.; Chu, Z.-L.; Grottick,
A. J.; Hauser, E. K.; Leonard, J.; Jones, R. M. J. Med. Chem.
2008, 51, 5172.
15. Yang, Z.; Fang, Y.; Pham, T.-A. N.; Lee, J.; Park, H. Bioorg. Med.
Chem. Lett. 2013, 23, 1519.
Acknowledgments
16. Li, C.; Ren, S.-F.; Hou, J.-L.; Yi, H.-P.; Zhu, S.-Z.; Jiang, X.-K.;
Li, Z.-T. Angw. Chem. Int. Ed. 2005, 44, 5725. Downfield chemi-
cal shift of the NH signal of compound 4 (δ 7.42 ppm) compared
with that of the non-substituted compound (δ 7.36 ppm) suggested
the formation of the H-F intramolecular hydrogen bond.
17. (a) Kobayashi, T.; Suemasa, A.; Igawa, A.; Ide, S.; Fukuda, H.;
Abe, H.; Arisawa, M.; Minami, M.; Shuto, S. Med. Chem. Lett.
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We thank Dr. S. Tanabe, Director of Tokyo New Drug Re-
search Laboratories, Executive Officer, Member of the Board,
Kowa Co., Ltd., for his support and encouragement.
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