6-Substituted quinolines as RORγt inverse agonists. Issue 23 (1st December 2017)

• Record Type: Journal Article
• Authors: Barbay, J. Kent; Cummings, Maxwell D.; Abad, Marta; Castro, Glenda; Kreutter, Kevin D.; Kummer, David A.; Maharoof, Umar; Milligan, Cynthia; Nishimura, Rachel; Pierce, Joan; Schalk-Hihi, Celine; Spurlino, John; Tanis, Virginia M.; Urbanski, Maud; Venkatesan, Hariharan; Wang, Aihua; Woods, Craig; Wolin, Ronald; Xue, Xiaohua; Edwards, James P.; Fourie, Anne M.; Leonard, Kristi
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 23(2017)
• Page Start: 5277
• Page End: 5283
• Publication Date: 2017-12-01
• Subjects: RORγt -- Retinoic acid-related orphan nuclear receptor gamma t -- Th17 -- IL-17; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.10.027
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: We identified 6-substituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). The synthesis of this class of RORγt modulators is reported, and optimization of the substituents at the quinoline 6-position that produced compounds with high affinity for the receptor is detailed. This effort identified molecules that act as potent, full inverse agonists in a RORγt-driven cell-based reporter assay. The X-ray crystal structures of two full inverse agonists from this chemical series bound to the RORγt ligand binding domain are disclosed, and we highlight the interaction of a hydrogen-bond acceptor on the 6-position substituent of the inverse agonist with Glu379:NH as a conserved binding contact.