Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists.

Autor:	Shi J; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Gu Z; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Jurica EA; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Wu X; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Haque LE; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Williams KN; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Hernandez AS; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Hong Z; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Gao Q; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Dabros M; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Davulcu AH; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Mathur A; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Rampulla RA; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Gupta AK; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Jayaram R; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Apedo A; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Moore DB; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Liu H; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Kunselman LK; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Brady EJ; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Wilkes JJ; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Zinker BA; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Cai H; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Shu YZ; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Sun Q; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Dierks EA; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Foster KA; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Xu C; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Wang T; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Panemangalore R; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Cvijic ME; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Xie C; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Cao GG; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Zhou M; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Krupinski J; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Whaley JM; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Robl JA; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Ewing WR; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Ellsworth BA; Research and Development, Bristol-Myers Squibb Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2018 Feb 08; Vol. 61 (3), pp. 681-694. Date of Electronic Publication: 2018 Jan 27.
DOI:	10.1021/acs.jmedchem.7b00982
Abstrakt:	G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp 3 /sp 2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.
Databáze:	MEDLINE
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