Design, Synthesis, andAntidiabetic Activity of 4-Phenoxynicotinamideand 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potentand Orally Efficacious TGR5 Agonists.

4-Phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamidederivativesas potent and orally efficacious TGR5 agonists are reported. Several4-phenoxynicotinamide derivatives were found to activate human andmouse TGR5 (hTGR5 and mTGR5) with EC50values in the lownanomolar range. Compound 23g, with an EC50value of 0.72 nM on hTGR5 and an EC50value of 6.2 nMon mTGR5, was selected for further in vivo efficacy studies. Thiscompound exhibited a significant dose-dependent glucagon-like peptide-1(GLP-1) secretion effect. A single oral dose of 23g(50mg/kg) significantly reduced blood glucose levels in db/dbmice and caused a 49% reduction in the area under the blood glucosecurve (AUC)0–120 minfollowing an oral glucosetolerance test (OGTT) in imprinting control region (ICR) mice. However, 23gstimulated gallbladder filling, which might result inside effects to the gallbladder. [ABSTRACT FROM AUTHOR]