Sameer Agarwal
Cadila Healthcare Ltd., India
Title: Discovery of novel 2-thio-imidazole derivatives as potent and orally efficacious TGR5 receptor agonists
Biography
Biography: Sameer Agarwal
Abstract
TGR5 is a G protein-coupled receptor (GPCR), activation of which promotes secretion of glucagon-like peptide-1 (GLP-1) and modulates insulin secretion. In our pursuit of novel drugs with distinct mechanism of action for type 2 diabetes we report here the discovery of 2-((2-(4-(1H-imidazol-1-yl) phenoxy) ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole as a novel, potent, selective and orally bioavailable TGR5 agonist. Using computer aided modeling studies we designed a series of novel 2-thio-imidazole derivatives, and then experimentally established a structure-activity relationship (SAR). The mentioned compound was identified as a TGR5 agonist with EC50 of 57pM and 62pM against the human TGR5 and mouse TGR5 receptors, respectively, in recombinant CRE-directed luciferase reporter gene assays. The compound showed a favorable pharmacokinetic profile. Further, this compound showed in vivo GLP-1 secretion in a C57 mouse model, and it potently reduced glucose excursion in oral glucose tolerance test (OGTT) in DIO C57 mice (ED50 = 7.9 mg/kg; ED90 = 29.2 mg/kg).
