title: Discovery of novel N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides as potent RORγt inhibitors.
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.
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China. Electronic address: wang.2.yonghui@gmail.com.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Guifeng
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Yaobang
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Yingli
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Sijie
authors.initials: S
authors.lastname: Lu
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Yong-Gang
authors.initials: YG
authors.lastname: Zhao
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Liuqing
authors.initials: L
authors.lastname: Yang
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Research and Development, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Orband-Miller
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Ruina
authors.initials: R
authors.lastname: Gao
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Melanie
authors.initials: M
authors.lastname: Huxdorf
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Jia-Ning
authors.initials: JN
authors.lastname: Xiang
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: John D
authors.initials: JD
authors.lastname: Elliott
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Stewart
authors.initials: S
authors.lastname: Leung
authors.affiliation: Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Xichen
authors.initials: X
authors.lastname: Lin
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy*; D002454:Cell Differentiation / Q000187:drug effects; D003094:Collagen; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D058504:Th17 Cells
chemical_list: D000577:Amides; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D003094:Collagen
keywords: Multiple sclerosis; RORγt inhibitor; Rheumatoid arthritis; Th17 cell differentiation