Discovery of Tertiary Amine and Indole Derivatives as Potent RORγt Inverse Agonists

Ting Yang; Qian Liu; Yaobang Cheng; Wei Cai; Yingli Ma; Liuqing Yang; Qianqian Wu; Lisa A Orband-Miller; Ling Zhou; Zhijun Xiang; Melanie Huxdorf; Wei Zhang; Jing Zhang; Jia-Ning Xiang; Stewart Leung; Yang Qiu; Zhong Zhong; John D Elliott; Xichen Lin; Yonghui Wang

doi:10.1021/ml4003875

Discovery of Tertiary Amine and Indole Derivatives as Potent RORγt Inverse Agonists

ACS Med Chem Lett. 2013 Nov 22;5(1):65-8. doi: 10.1021/ml4003875. eCollection 2014 Jan 9.

Authors

Ting Yang¹, Qian Liu¹, Yaobang Cheng¹, Wei Cai¹, Yingli Ma¹, Liuqing Yang¹, Qianqian Wu¹, Lisa A Orband-Miller², Ling Zhou¹, Zhijun Xiang¹, Melanie Huxdorf¹, Wei Zhang¹, Jing Zhang¹, Jia-Ning Xiang¹, Stewart Leung¹, Yang Qiu¹, Zhong Zhong¹, John D Elliott¹, Xichen Lin¹, Yonghui Wang¹

Affiliations

¹ Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
² Research and Development, GlaxoSmithKline , 5 Moore Drive, Research Triangle Park, North Carolina 27709, United States.

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.

Keywords: RORγt; Th17 cell differentiation; agonists; cocrystal structure; inverse agonists; structure-based design.