Discovery of novel N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides as potent RORγt inhibitors

Novel series of N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides were discovered as potent retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitors. SAR studies of the RORγt HTS hit 6a led to identification of thiazole ketone amide 8h and thiophene...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2014-01, Vol.22 (2), p.692-702
Hauptverfasser:	Wang, Yonghui, Cai, Wei, Zhang, Guifeng, Yang, Ting, Liu, Qian, Cheng, Yaobang, Zhou, Ling, Ma, Yingli, Cheng, Ziqiang, Lu, Sijie, Zhao, Yong-Gang, Zhang, Wei, Xiang, Zhijun, Wang, Shuai, Yang, Liuqing, Wu, Qianqian, Orband-Miller, Lisa A., Xu, Yan, Zhang, Jing, Gao, Ruina, Huxdorf, Melanie, Xiang, Jia-Ning, Zhong, Zhong, Elliott, John D., Leung, Stewart, Lin, Xichen
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Amides - administration & dosage Amides - chemistry Amides - pharmacology Animals Arthritis - chemically induced Arthritis - drug therapy Cell Differentiation - drug effects Collagen Disease Models, Animal Dose-Response Relationship, Drug Drug Discovery Encephalomyelitis, Autoimmune, Experimental - drug therapy Humans Mice Molecular Structure Multiple sclerosis Nuclear Receptor Subfamily 1, Group F, Member 3 - antagonists & inhibitors Rheumatoid arthritis RORγt inhibitor Structure-Activity Relationship Th17 cell differentiation Th17 Cells
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Zusammenfassung:	Novel series of N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides were discovered as potent retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitors. SAR studies of the RORγt HTS hit 6a led to identification of thiazole ketone amide 8h and thiophene ketone amide 9g with high binding affinity and inhibitory activity of Th17 cell differentiation. Compound 8h showed in vivo efficacy in both mouse experimental autoimmune encephalomyelitis (EAE) and collagen induced arthritis (CIA) models via oral administration.
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2013.12.021