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
Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
Bioorg Med Chem. 2014 Jan 15;22(2):692-702. doi: 10.1016/j.bmc.2013.12.021. Epub 2013 Dec 21.
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.
新型的N-(5-(芳基羰基)噻唑-2-基)酰胺和N-(5-(芳基羰基)噻吩-2-基)酰胺系列被发现是有效的视黄酸受体相关孤儿受体-γ-t（RORγt）抑制剂。对RORγt高通量筛选命中物6a的构效关系研究导致了具有高结合亲和力和抑制Th17细胞分化活性的噻唑酮酰胺8h和噻吩酮酰胺9g的鉴定。化合物8h通过口服给药在小鼠实验性自身免疫性脑脊髓炎（EAE）和胶原诱导的关节炎（CIA）模型中均显示出体内疗效。
