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Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode.
Jurica, Elizabeth A; Wu, Ximao; Williams, Kristin N; Hernandez, Andres S; Nirschl, David S; Rampulla, Richard A; Mathur, Arvind; Zhou, Min; Cao, Gary; Xie, Chunshan; Jacob, Biji; Cai, Hong; Wang, Tao; Murphy, Brian J; Liu, Heng; Xu, Carrie; Kunselman, Lori K; Hicks, Michael B; Sun, Qin; Schnur, Dora M; Sitkoff, Doree F; Dierks, Elizabeth A; Apedo, Atsu; Moore, Douglas B; Foster, Kimberly A; Cvijic, Mary Ellen; Panemangalore, Reshma; Flynn, Neil A; Maxwell, Brad D; Hong, Yang; Tian, Yuan; Wilkes, Jason J; Zinker, Bradley A; Whaley, Jean M; Barrish, Joel C; Robl, Jeffrey A; Ewing, William R; Ellsworth, Bruce A.
Afiliação
  • 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.
J Med Chem ; 60(4): 1417-1431, 2017 02 23.
Article em En | MEDLINE | ID: mdl-28112924
ABSTRACT
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-CF3 to the pyrrolidine improves the human GPR40 binding Ki 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 Gq-coupled intracellular Ca2+ flux and Gs-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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirrolidinas / Receptores Acoplados a Proteínas G / Hipoglicemiantes Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirrolidinas / Receptores Acoplados a Proteínas G / Hipoglicemiantes Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2017 Tipo de documento: Article