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

  • Bioorg Med Chem. 2014 Jan 15;22(2):692-702. doi: 10.1016/j.bmc.2013.12.021.
Yonghui Wang  1 ,  Wei Cai  2 ,  Guifeng Zhang  2 ,  Ting Yang  2 ,  Qian Liu  2 ,  Yaobang Cheng  2 ,  Ling Zhou  2 ,  Yingli Ma  2 ,  Ziqiang Cheng  2 ,  Sijie Lu  2 ,  Yong-Gang Zhao  2 ,  Wei Zhang  2 ,  Zhijun Xiang  2 ,  Shuai Wang  2 ,  Liuqing Yang  2 ,  Qianqian Wu  2 ,  Lisa A Orband-Miller  3 ,  Yan Xu  2 ,  Jing Zhang  2 ,  Ruina Gao  2 ,  Melanie Huxdorf  2 ,  Jia-Ning Xiang  2 ,  Zhong Zhong  2 ,  John D Elliott  2 ,  Stewart Leung  2 ,  Xichen Lin  2
Affiliations
  • 1. Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China. Electronic address: [email protected].
  • 2. Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
  • 3. Research and Development, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
PMID: 24388993 DOI: 10.1016/j.bmc.2013.12.021
Abstract

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.

Keywords
Multiple sclerosis; RORγt inhibitor; Rheumatoid arthritis; Th17 cell differentiation.
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