Discovery of N -(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists
| Autor: | Wei Zhang, Sijie Lu, Ling Zhou, Jia-Ning Xiang, Qian Liu, Yingli Ma, John D. Elliott, Stewart Leung, Yi Li, Liuqing Yang, Feng Ren, Kathleen Zhang, Wang Yonghui, Lisa A. Orband-Miller, Xichen Lin, Zhijun Xiang, Ziqiang Cheng, Qianqian Wu, Ting Yang |
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| Rok vydání: | 2015 |
| Předmět: |
Drug Inverse Agonism
Stereochemistry Cellular differentiation Clinical Biochemistry Pharmaceutical Science Biochemistry Partial agonist Mice chemistry.chemical_compound RAR-related orphan receptor gamma Drug Discovery Animals Humans Inverse agonist Molecular Biology Liver microsomes Cells Cultured Aryl Organic Chemistry Cell Differentiation Nuclear Receptor Subfamily 1 Group F Member 3 Amides Combinatorial chemistry Molecular Docking Simulation Thiazoles chemistry Th17 Cells Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry. 23:5293-5302 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2015.07.068 |
| Popis: | A novel series of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as RORγt inverse agonists was discovered. Binding mode analysis of a RORγt partial agonist (2c) revealed by co-crystal structure in RORγt LBD suggests that the inverse agonists do not directly interfere with the interaction between H12 and the RORγt LBD. Detailed SAR exploration led to identification of potent RORγt inverse agonists such as 3m with a pIC50 of 8.0. Selected compounds in the series showed reasonable activity in Th17 cell differentiation assay as well as low intrinsic clearance in mouse liver microsomes. |
| Databáze: | OpenAIRE |
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