Discovery of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists

• Published in: Bioorganic & medicinal chemistry Vol. 23; no. 17; pp. 5293 - 5302
• Main Authors: Wang, Yonghui, Yang, Ting, Liu, Qian, Ma, Yingli, Yang, Liuqing, Zhou, Ling, Xiang, Zhijun, Cheng, Ziqiang, Lu, Sijie, Orband-Miller, Lisa A., Zhang, Wei, Wu, Qianqian, Zhang, Kathleen, Li, Yi, Xiang, Jia-Ning, Elliott, John D., Leung, Stewart, Ren, Feng, Lin, Xichen
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.09.2015; Elsevier
• Subjects: Amides - chemistry; Amides - pharmacology; Animals; Biochemistry & Molecular Biology; Cell Differentiation - drug effects; Cells, Cultured; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Crystal structure; Drug Inverse Agonism; Humans; Life Sciences & Biomedicine; Mice; Molecular Docking Simulation; Nuclear Receptor Subfamily 1, Group F, Member 3 - agonists; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Pharmacology & Pharmacy; Physical Sciences; RORγt inverse agonists; Science & Technology; Th17 cell differentiation; Th17 Cells - cytology; Th17 Cells - drug effects; Thiazole ether amides; Thiazoles - chemistry; Thiazoles - pharmacology; RORγt inverse agonists; Thiazole ether amides; Th17 cell differentiation; Crystal structure; AUTOIMMUNE; MODULATORS; TARGETING TH17 CELLS; ROR gamma t inverse agonists; DIFFERENTIATION; INHIBITORS; IDENTIFICATION; DERIVATIVES; AMIDES
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.07.068

[Display omitted] 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.