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

被引：57

作者：

Wang, Yonghui ^{[1
]}

Cai, Wei ^{[1
]}

Zhang, Guifeng ^{[1
]}

Yang, Ting ^{[1
]}

Liu, Qian ^{[1
]}

Cheng, Yaobang ^{[1
]}

Zhou, Ling ^{[1
]}

Ma, Yingli ^{[1
]}

Cheng, Ziqiang ^{[1
]}

Lu, Sijie ^{[1
]}

Zhao, Yong-Gang ^{[1
]}

Zhang, Wei ^{[1
]}

Xiang, Zhijun ^{[1
]}

Wang, Shuai ^{[1
]}

Yang, Liuqing ^{[1
]}

Wu, Qianqian ^{[1
]}

Orband-Miller, Lisa A. ^{[2
]}

Xu, Yan ^{[1
]}

Zhang, Jing ^{[1
]}

Gao, Ruina ^{[1
]}

Huxdorf, Melanie ^{[1
]}

Xiang, Jia-Ning ^{[1
]}

Zhong, Zhong ^{[1
]}

Elliott, John D. ^{[1
]}

Leung, Stewart ^{[1
]}

Lin, Xichen ^{[1
]}

机构：

[1] GlaxoSmithKline, Res & Dev, Shanghai 201203, Peoples R China

[2] GlaxoSmithKline, Res & Dev, Res Triangle Pk, NC 27709 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2014年 / 22卷 / 02期

关键词：

ROR gamma t inhibitor; Th17 cell differentiation; Multiple sclerosis; Rheumatoid arthritis; ORPHAN NUCLEAR RECEPTORS; TH17; CELLS; DIFFERENTIATION; INTERLEUKIN-17; IDENTIFICATION; AUTOIMMUNE; IL-17; ARTHRITIS; ALPHA;

D O I：

10.1016/j.bmc.2013.12.021

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 (ROR gamma t) inhibitors. SAR studies of the ROR gamma t 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. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：692 / 702

页数：11

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