Discovery of a Potent and Orally Efficacious TGR5 Receptor Agonist

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• 作者：Sameer Agarwal ; Amit Patil ; Umesh Aware ; Prashant Deshmukh ; Brijesh Darji ; Santosh Sasane ; Kalapatapu V. V. M. Sairam ; Priyanka Priyadarsiny ; Poonam Giri ; Harilal Patel ; Suresh Giri ; Mukul Jain ; Ranjit C. Desai
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：January 14, 2016
• 年：2016
• 卷：7
• 期：1
• 页码：51-55
• 全文大小：350K
• ISSN：1948-5875

文摘

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.