title: Design, synthesis, and structure-activity relationships of 3,4,5-trisubstituted 4,5-dihydro-1,2,4-oxadiazoles as TGR5 agonists.
abstract: Given its role in the mediation of energy and glucose homeostasis, the G-protein-coupled bile acid receptor 1 (TGR5) is considered a potential target for the treatment of type 2 diabetes mellitus and other metabolic disorders. By thorough analysis of diverse structures of published TGR5 agonists, a hypothetical ligand-based pharmacophore model was built, and a new class of potent TGR5 agonists, based on the novel 3,4,5-trisubstituted 4,5-dihydro-1,2,4-oxadiazole core, was discovered by rational design. Three distinct synthetic methods for constructing 4,5-dihydro-1,2,4-oxadiazoles and extensive structure-activity relationship studies are reported herein. Compound (R)-54 n, the structure of which was determined by single-crystal X-ray diffraction and quantum chemical solid-state TDDFT-ECD calculations, showed the best potency, with an EC50 value of 1.4 nM toward hTGR5. Its favorable properties in vitro warrant further investigation.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Zhu
authors.forename: Yangliang
authors.initials: Y
authors.lastname: Ye
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Ning
authors.forename: Attila
authors.initials: A
authors.lastname: Mándi
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.forename: Qingan
authors.initials: Q
authors.lastname: Zou
authors.forename: Tibor
authors.initials: T
authors.lastname: Kurtán
authors.forename: Ying
authors.initials: Y
authors.lastname: Leng
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011789:Quantum Theory; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C000589460:5-(2-chloro-3,5-bis(trifluoromethyl)phenyl)-4-((4-(2,6-difluorophenyl)pyridin-3-yl)methyl)-3-(furan-2-yl)-4,5-dihydro-1,2,4-oxadiazole; C473772:GPBAR1 protein, human; D010069:Oxadiazoles; D043562:Receptors, G-Protein-Coupled