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Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode.
- Source :
-
Journal of Medicinal Chemistry . 2/23/2017, Vol. 60 Issue 4, p1417-1431. 15p. - Publication Year :
- 2017
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00222623
- Volume :
- 60
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 121439596
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.6b01559