Identification of N-sulfonyl-tetrahydroquinolines as RORc inverse agonists

Bioorg Med Chem Lett. 2015 Oct 1;25(19):4109-13. doi: 10.1016/j.bmcl.2015.08.028. Epub 2015 Aug 14.

Abstract

A high-throughput screen of the Genentech/Roche compound collection using a retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) biochemical assay revealed a N-sulfonyl-tetrahydroquinoline hit. Herein, we describe the hit-to-lead optimization and structure-activity relationships of these tetrahydroquinoline RORc inverse agonists. Through iterative synthesis and analog design, we identified compounds with improved biochemical RORc inverse agonist activity and RORc cellular potencies. These improved N-sulfonyl-tetrahydroquinoline compounds also exhibited selectivity for RORc over other nuclear receptors.

Keywords: Autoimmune; IL-17; Inflammation; RORc; RORγ.

MeSH terms

  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Inverse Agonism*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists*
  • Quinolines / chemical synthesis
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Structure-Activity Relationship

Substances

  • N-sulfonyl-tetrahydroquinoline
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Quinolines
  • RORC protein, human