Design of Gut-Restricted Thiazolidine Agonists of G Protein-Coupled Bile Acid Receptor 1 (GPBAR1, TGR5)

Journal of Medicinal Chemistry
Tao ChenJason Gustaf Lewis

Abstract

Bile acid signaling and metabolism in the gastrointestinal tract have wide-ranging influences on systemic disease. G protein-coupled bile acid receptor 1 (GPBAR1, TGR5) is one of the major effectors in bile acid sensing, with demonstrated influence on metabolic, inflammatory, and proliferative processes. The pharmacologic utility of TGR5 agonists has been limited by systemic target-related effects such as excessive gallbladder filling and blockade of gallbladder emptying. Gut-restricted TGR5 agonists, however, have the potential to avoid these side effects and consequently be developed into drugs with acceptable safety profiles. We describe the discovery and optimization of a series of gut-restricted TGR5 agonists that elicit a potent response in mice, with minimal gallbladder-related effects. The series includes 12 (TGR5 EC50: human, 143 nM; mouse, 1.2 nM), a compound with minimal systemic availability that may have therapeutic value to patients with type 2 diabetes mellitus, nonalcoholic steatohepatitis, or inflammatory bowel disease.

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Citations

Jan 4, 2019·American Journal of Physiology. Gastrointestinal and Liver Physiology·Patricia D FinnJason G Lewis
Oct 27, 2018·Frontiers in Endocrinology·Silvano Paternoster, Marco Falasca
Jan 14, 2021·Bioorganic & Medicinal Chemistry·Shizhen ZhaoWei-Dong Chen
May 22, 2020·ACS Medicinal Chemistry Letters·Simona De MarinoStefano Fiorucci
May 29, 2021·RSC Medicinal Chemistry·Ali NakhiPeter I Dosa

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