Journal of Medicinal Chemistry p. 1417 - 1431 (2017)
Update date:2022-08-15
Topics:
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.
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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