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Discovery of Tertiary Amine and Indole Derivatives as Potent ROR?t Inverse Agonists.

ABSTRACT: A novel series of tertiary amines as retinoid-related orphan receptor gamma-t (ROR?t) inverse agonists was discovered through agonist/inverse agonist conversion. The level of ROR?t inhibition can be enhanced by modulating the conformational disruption of H12 in ROR?t LBD. Linker exploration and rational design led to the discovery of more potent indole-based ROR?t inverse agonists.

SUBMITTER: Yang T

PROVIDER: S-EPMC4027777 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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

Yang Ting T Liu Qian Q Cheng Yaobang Y Cai Wei W Ma Yingli Y Yang Liuqing L Wu Qianqian Q Orband-Miller Lisa A LA Zhou Ling L Xiang Zhijun Z Huxdorf Melanie M Zhang Wei W Zhang Jing J Xiang Jia-Ning JN Leung Stewart S Qiu Yang Y Zhong Zhong Z Elliott John D JD Lin Xichen X Wang Yonghui Y

ACS medicinal chemistry letters 20131122 1

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. ...[more]

PMID: 24900774

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