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Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode
Journal article   Open access   Peer reviewed

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

Elizabeth A Jurica, Ximao Wu, Kristin N Williams, Andres S Hernandez, David S Nirschl, Richard A Rampulla, Arvind Mathur, Min Zhou, Gary Cao, Chunshan Xie, …
Journal of medicinal chemistry, v 60(4), pp 1417-1431
23 Feb 2017
DOI: https://doi.org/10.1021/acs.jmedchem.6b01559
PMID: 28112924
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.7270/q25x2cd5View
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Abstract

Animals Blood Glucose - analysis Blood Glucose - metabolism Cell Line Cells, Cultured Diabetes Mellitus, Type 2 - blood Diabetes Mellitus, Type 2 - drug therapy Diabetes Mellitus, Type 2 - metabolism Glucagon-Like Peptide 1 - metabolism Humans Hypoglycemic Agents - chemistry Hypoglycemic Agents - pharmacokinetics Hypoglycemic Agents - pharmacology Hypoglycemic Agents - therapeutic use Insulin - metabolism Male Mice, Inbred C57BL Models, Molecular Pyrrolidines - chemistry Pyrrolidines - pharmacokinetics Pyrrolidines - pharmacology Pyrrolidines - therapeutic use Rats Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - metabolism
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 to the pyrrolidine improves the human GPR40 binding K 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 -coupled intracellular Ca flux and G -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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#3 Good Health and Well-Being

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Web of Science research areas
Chemistry, Medicinal
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