title: Discovery of Tertiary Amine and Indole Derivatives as Potent RORγt Inverse Agonists.
abstract: A novel series of tertiary amines as retinoid-related orphan receptor gamma-t (RORγt) inverse agonists was discovered through agonist/inverse agonist conversion. The level of RORγt inhibition can be enhanced by modulating the conformational disruption of H12 in RORγt LBD. Linker exploration and rational design led to the discovery of more potent indole-based RORγt inverse agonists.
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: 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: 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: 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, North Carolina 27709, United States.
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: 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: 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: 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: 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: 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: 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: 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: Yang
authors.initials: Y
authors.lastname: Qiu
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: Xichen
authors.initials: X
authors.lastname: Lin
authors.affiliation: Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Wang
keywords: RORγt; Th17 cell differentiation; agonists; cocrystal structure; inverse agonists; structure-based design