Therapeutics: G protein-coupled bile acid receptor 1 (GPBAR1; TGR5); glucagon-like peptide 1 (GLP-1)

Mouse studies have identified a 4-phenoxynicotinamide-based TGR5 agonist that could help treat diabetes without the systemic side-effects of existing TGR5 ligands. Synthesis and in vitro testing of 4-phenoxynicotinamide analogs identified a lead compound with low intestinal absorption that agonized TGR5 with an EC50 of 25 nM. In normal mice, the compound increased GLP-1 secretion and glucose tolerance compared with vehicle, without causing systemic side effects. Also in the mice, the compound plus linagliptin increased GLP-1 secretion compared with either agent alone. Next steps could include evaluating the safety of the TGR5 agonist in preclinical models of diabetes...