2. Academic Validation
  3. 6-Substituted quinolines as RORγt inverse agonists

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

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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