Dataset Information

Novel Tricyclic Pyroglutamide Derivatives as Potent RORγt Inverse Agonists Identified using a Virtual Screening Approach.

ABSTRACT: Employing a virtual screening approach, we identified the pyroglutamide moiety as a nonacid replacement for the cyclohexanecarboxylic acid group which, when coupled to our previously reported conformationally locked tricyclic core, provided potent and selective RORγt inverse agonists. Structure-activity relationship optimization of the pyroglutamide moiety led to the identification of compound 18 as a potent and selective RORγt inverse agonist, albeit with poor aqueous solubility. We took advantage of the tertiary carbinol group in 18 to synthesize a phosphate prodrug, which provided good solubility, excellent exposures in mouse PK studies, and significant efficacy in a mouse model of psoriasis.

SUBMITTER: Liu Q

PROVIDER: S-EPMC7734821 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Novel Tricyclic Pyroglutamide Derivatives as Potent RORγt Inverse Agonists Identified using a Virtual Screening Approach.

Liu Qingjie Q Batt Douglas G DG Weigelt Carolyn A CA Yip Shiuhang S Wu Dauh-Rurng DR Ruzanov Max M Sack John S JS Wang Jinhong J Yarde Melissa M Li Sha S Shuster David J DJ Xie Jenny H JH Sherry Tara T Obermeier Mary T MT Fura Aberra A Stefanski Kevin K Cornelius Georgia G Khandelwal Purnima P Tino Joseph A JA Macor John E JE Salter-Cid Luisa L Denton Rex R Zhao Qihong Q Dhar T G Murali TGM

ACS medicinal chemistry letters 20201106 12

Employing a virtual screening approach, we identified the pyroglutamide moiety as a nonacid replacement for the cyclohexanecarboxylic acid group which, when coupled to our previously reported conformationally locked tricyclic core, provided potent and selective RORγt inverse agonists. Structure-activity relationship optimization of the pyroglutamide moiety led to the identification of compound <b>18</b> as a potent and selective RORγt inverse agonist, albeit with poor aqueous solubility. We took ...[more]

PMID: 33335675

Dataset Information

Novel Tricyclic Pyroglutamide Derivatives as Potent RORγt Inverse Agonists Identified using a Virtual Screening Approach.

Publications

Novel Tricyclic Pyroglutamide Derivatives as Potent RORγt Inverse Agonists Identified using a Virtual Screening Approach.

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