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Discovery of a Potent and Orally Efficacious TGR5 Receptor Agonist.

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. The 2-thio-imidazole derivative 6g was identified as a novel, potent, and selective TGR5 agonist (hTGR5 EC50 = 57 pM, mTGR5 = 62 pM) with a favorable pharmacokinetic profile. The compound 6g was found to have potent glucose lowering effects in vivo during an oral glucose tolerance test in DIO C57 mice with ED50 of 7.9 mg/kg and ED90 of 29.2 mg/kg.

SUBMITTER: Agarwal S

PROVIDER: S-EPMC4716599 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Discovery of a Potent and Orally Efficacious TGR5 Receptor Agonist.

Agarwal Sameer S Patil Amit A Aware Umesh U Deshmukh Prashant P Darji Brijesh B Sasane Santosh S Sairam Kalapatapu V V M KV Priyadarsiny Priyanka P Giri Poonam P Patel Harilal H Giri Suresh S Jain Mukul M Desai Ranjit C RC

ACS medicinal chemistry letters 20151120 1

TGR5 is a G protein-coupled receptor (GPCR), activation of which promotes secretion of glucagon-like peptide-1 (GLP-1) and modulates insulin secretion. The 2-thio-imidazole derivative 6g was identified as a novel, potent, and selective TGR5 agonist (hTGR5 EC50 = 57 pM, mTGR5 = 62 pM) with a favorable pharmacokinetic profile. The compound 6g was found to have potent glucose lowering effects in vivo during an oral glucose tolerance test in DIO C57 mice with ED50 of 7.9 mg/kg and ED90 of 29.2 mg/kg ...[more]

PMID: 26819665

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