title: Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode.
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-CF3to the pyrrolidine improves the human GPR40 binding Kiand 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.
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Elizabeth A
authors.identifier: 0000-0003-3689-5451
authors.initials: EA
authors.lastname: Jurica
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Ximao
authors.initials: X
authors.lastname: Wu
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Kristin N
authors.initials: KN
authors.lastname: Williams
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Andres S
authors.initials: AS
authors.lastname: Hernandez
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: David S
authors.initials: DS
authors.lastname: Nirschl
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Rampulla
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Arvind
authors.initials: A
authors.lastname: Mathur
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Gary
authors.initials: G
authors.lastname: Cao
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Chunshan
authors.initials: C
authors.lastname: Xie
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Biji
authors.initials: B
authors.lastname: Jacob
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Cai
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Murphy
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Heng
authors.initials: H
authors.lastname: Liu
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Carrie
authors.initials: C
authors.lastname: Xu
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Lori K
authors.initials: LK
authors.lastname: Kunselman
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Hicks
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Qin
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Dora M
authors.initials: DM
authors.lastname: Schnur
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Doree F
authors.initials: DF
authors.lastname: Sitkoff
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Dierks
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Atsu
authors.initials: A
authors.lastname: Apedo
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Moore
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Foster
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Cvijic
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Reshma
authors.initials: R
authors.lastname: Panemangalore
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Flynn
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Brad D
authors.identifier: 0000-0001-8507-2078
authors.initials: BD
authors.lastname: Maxwell
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Wilkes
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Zinker
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Whaley
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: William R
authors.initials: WR
authors.lastname: Ewing
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 4000, Princeton, New Jersey 08540-4000, United States.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ellsworth
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011759:Pyrrolidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; C473034:FFAR1 protein, human; D007004:Hypoglycemic Agents; D007328:Insulin; D011759:Pyrrolidines; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1