Design, synthesis and biological evaluation of a novel class of potent TGR5 agonists based on a 4-phenyl pyridine scaffold

• A new class of TGR5 agonists based on a 4-phenyl pyridine scaffold was designed and synthesized.
• Structure–activity relationships of this series were summarized.
• Several compounds, like 15a, 18b and 18c, showed excellent potency in vitro.
• 15a displayed an unfavorable PK profile and was found to be ineffective during an OGTT in ICR mice at a dose of 50 mg/kg.

TGR5, a GPCR, is involved in energy and glucose homeostasis, and as such, is a target for the treatment of diabetes, obesity and other metabolic syndromes. A new class of TGR5 agonists based on a 4-phenyl pyridine scaffold was designed, synthesized and evaluated in vitro and in vivo. Extensive structure–activity relationship studies are reported herein. The most potent compounds 15a, 18b and 18c showed comparable activity with the lead compound 2. 15a had the best potency in vitro but displayed an unfavorable pharmacokinetic profile and was found to be ineffective during an oral glucose tolerance test in imprinting control region mice at a dose of 50 mg/kg.

A novel class of amides, sulfonamides and α-amino nitriles as potent TGR5 agonists was evaluated in vitro and in vivo.Figure optionsDownload as PowerPoint slide