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.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Zhu J,Ye Y,Ning M,Mándi A,Feng Y,Zou Q,Kurtán T,Leng Y,Shen Jdoi
10.1002/cmdc.201300144subject
Has Abstractpub_date
2013-07-01 00:00:00pages
1210-23issue
7eissn
1860-7179issn
1860-7187journal_volume
8pub_type
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