Discovery of Biaryl Amides as Potent, Orally Bioavailable, and CNS Penetrant RORγt Inhibitors

  • ACS Med Chem Lett. 2015 May 26;6(7):787-92. doi: 10.1021/acsmedchemlett.5b00122.
Yonghui Wang  1 ,  Wei Cai  2 ,  Yaobang Cheng  2 ,  Ting Yang  2 ,  Qian Liu  2 ,  Guifeng Zhang  2 ,  Qinghua Meng  2 ,  Fangbin Han  2 ,  Yafei Huang  1 ,  Ling Zhou  2 ,  Zhijun Xiang  2 ,  Yong-Gang Zhao  2 ,  Yan Xu  2 ,  Ziqiang Cheng  2 ,  Sijie Lu  2 ,  Qianqian Wu  2 ,  Jia-Ning Xiang  2 ,  John D Elliott  2 ,  Stewart Leung  2 ,  Feng Ren  2 ,  Xichen Lin  2
Affiliations
  • 1. School of Pharmacy, Fudan University , 826 Zhangheng Road, Pudong, Shanghai 201203, China.
  • 2. Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
PMID: 26191367 DOI: 10.1021/acsmedchemlett.5b00122
Abstract

A novel series of biaryl amides was identified as RORγt inhibitors through core replacement of a starting hit 1. Structure-activity relationship exploration on the biaryl moiety led to discovery of potent RORγt inhibitors with good oral bioavailability and CNS penetration. Compounds 9a and 9g demonstrated excellent in vivo efficacy in EAE mice dose dependently with once daily oral administration.

Keywords
EAE; RORγt inhibitor; Th17 cell differentiation; biaryl amides; multiple sclerosis.
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