| Literature DB >> 29079472 |
J Kent Barbay1, Maxwell D Cummings2, Marta Abad3, Glenda Castro4, Kevin D Kreutter5, David A Kummer4, Umar Maharoof5, Cynthia Milligan3, Rachel Nishimura4, Joan Pierce4, Celine Schalk-Hihi3, John Spurlino3, Virginia M Tanis4, Maud Urbanski5, Hariharan Venkatesan4, Aihua Wang5, Craig Woods4, Ronald Wolin4, Xiaohua Xue4, James P Edwards4, Anne M Fourie4, Kristi Leonard5.
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.Entities:
Keywords: IL-17; RORγt; Retinoic acid-related orphan nuclear receptor gamma t; Th17
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Year: 2017 PMID： 29079472 DOI： 10.1016/j.bmcl.2017.10.027
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823