6-Substituted quinolines as RORγt inverse agonists

  • Bioorg Med Chem Lett. 2017 Dec 1;27(23):5277-5283. doi: 10.1016/j.bmcl.2017.10.027.
J Kent Barbay  1 ,  Maxwell D Cummings  2 ,  Marta Abad  3 ,  Glenda Castro  4 ,  Kevin D Kreutter  5 ,  David A Kummer  4 ,  Umar Maharoof  5 ,  Cynthia Milligan  3 ,  Rachel Nishimura  4 ,  Joan Pierce  4 ,  Celine Schalk-Hihi  3 ,  John Spurlino  3 ,  Virginia M Tanis  4 ,  Maud Urbanski  5 ,  Hariharan Venkatesan  4 ,  Aihua Wang  5 ,  Craig Woods  4 ,  Ronald Wolin  4 ,  Xiaohua Xue  4 ,  James P Edwards  4 ,  Anne M Fourie  4 ,  Kristi Leonard  5
Affiliations
  • 1. Discovery Immunology, Janssen Research and Development, LLC, Welsh and McKean Roads, Spring House, PA 19477, United States. Electronic address: [email protected].
  • 2. Discovery Sciences, Janssen Research and Development, LLC, Welsh and McKean Roads, Spring House, PA 19477, United States. Electronic address: [email protected].
  • 3. Discovery Sciences, Janssen Research and Development, LLC, Welsh and McKean Roads, Spring House, PA 19477, United States.
  • 4. Discovery Immunology, Janssen Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.
  • 5. Discovery Immunology, Janssen Research and Development, LLC, Welsh and McKean Roads, Spring House, PA 19477, United States.
PMID: 29079472 DOI: 10.1016/j.bmcl.2017.10.027
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.

Keywords
IL-17; RORγt; Retinoic acid-related orphan nuclear receptor gamma t; Th17.
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