Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode.

Autor:	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., 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., Nirschl DS; 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., Mathur A; 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., Cao G; 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., Jacob B; 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., Wang T; Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Murphy BJ; 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., Xu C; 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., Hicks MB; 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., Schnur DM; Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Sitkoff DF; 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., 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., Foster KA; 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., Panemangalore R; Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Flynn NA; Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Maxwell BD; Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Hong Y; Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Tian Y; 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., Whaley JM; Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States., Barrish JC; 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] 2017 Feb 23; Vol. 60 (4), pp. 1417-1431. Date of Electronic Publication: 2017 Feb 09.
DOI:	10.1021/acs.jmedchem.6b01559
Abstrakt:	A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF 3 to the pyrrolidine improves the human GPR40 binding K i and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both G q -coupled intracellular Ca 2+ flux and G s -coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.
Databáze:	MEDLINE
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