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

Basic Information

ID: ALA4196171

Journal: J Med Chem

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

Authors: Chen T, Reich NW, Bell N, Finn PD, Rodriguez D, Kohler J, Kozuka K, He L, Spencer AG, Charmot D, Navre M, Carreras CW, Koo-McCoy S, Tabora J, Caldwell JS, Jacobs JW, Lewis JG.

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.

CiteXplore: 30141927

DOI: 10.1021/acs.jmedchem.8b00308

Patent ID: ┄