title: Discovery and Structure-Activity Relationship Study of 4-Phenoxythiazol-5-carboxamides as Highly Potent TGR5 Agonists.
abstract: A novel therapy that stimulates endogenous glucagon-like peptide-1 (GLP-1) secretion by Takeda G-protein-coupled receptor 5 (TGR5) agonists might be a superior alternative for the treatment of type 2 diabetes mellitus. A series of 4-phenoxythiazol-5-carboxamides were developed as highly potent TGR5 agonists using a bioisosteric replacement strategy based on the scaffold of 4-phenoxynicotinamides. The structure-activity relationship on the bottom phenyl ring and the thiazole ring was extensively studied, and the 2-methyl-thiazole derivatives 30c and e displayed the best in vitro potency toward human TGR5, with EC50 values of approximately 1 nM. While endowed with excellent in vitro potency, the 2-methyl-thiazoles were flawed with high microsomal clearance.
authors: College of Pharmacy, Nanchang University.
authors: Zhixiang
authors: Z
authors: Chen
authors: Mengmeng
authors: M
authors: Ning
authors: Qingan
authors: Q
authors: Zou
authors: Hua
authors: H
authors: Cao
authors: Yangliang
authors: Y
authors: Ye
authors: Ying
authors: Y
authors: Leng
authors: Jianhua
authors: J
authors: Shen
mesh_terms: D055808:Drug Discovery; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C473772:GPBAR1 protein, human; D043562:Receptors, G-Protein-Coupled; D013844:Thiazoles