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: Junjie Zhu, Yangliang Ye, Mengmeng Ning, Attila Mándi, Ying Feng, Qingan Zou, Tibor Kurtán, Ying Leng, Jianhua Shen
• Journal: ChemMedChem (ChemMedChem) Vol. 8 Issue 7 Pg. 1210-23 (Jul 2013) ISSN: 1860-7187 [Electronic] Germany
• PMID: 23757200 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• 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
• GPBAR1 protein, human
• Oxadiazoles
• Receptors, G-Protein-Coupled

Topics

• Dose-Response Relationship, Drug
• Drug Design
• Drug Evaluation, Preclinical
• HEK293 Cells
• Humans
• Models, Molecular
• Molecular Structure
• Oxadiazoles (chemical synthesis, chemistry, pharmacology)
• Quantum Theory
• Receptors, G-Protein-Coupled (agonists)
• Structure-Activity Relationship