Discovery of a potent orally bioavailable retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitor, S18-000003

Bioorg Med Chem Lett. 2018 Dec 1;28(22):3549-3553. doi: 10.1016/j.bmcl.2018.09.032. Epub 2018 Sep 27.

Abstract

The retinoic acid receptor-related orphan receptor-gamma-t (RORγt) is the master transcription factor responsible for regulating the development and function of T-helper 17 (Th17) cells, which are related to the pathology of several autoimmune disorders. Therefore, RORγt is an attractive drug target for such Th17-mediated autoimmune diseases. A structure-activity relationship (SAR) study of lead compound 1 yielded a novel series of RORγt inhibitors, represented by compound 6. Detailed SAR optimization, informed by X-ray cocrystal structure analysis, led to the discovery of a potent orally bioavailable RORγt inhibitor 25, which inhibited IL-17 production in the skin of IL-23-treated mice by oral administration.

Keywords: Autoimmune disease; Cocrystal structure with ROR(γ)t LBD; IL-17; ROR(γ)t inhibitor; Th17 cell.

MeSH terms

  • Administration, Oral
  • Amides / chemistry*
  • Amides / pharmacokinetics
  • Amides / therapeutic use
  • Animals
  • Autoimmune Diseases / drug therapy
  • Binding Sites
  • Binding, Competitive
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Half-Life
  • Humans
  • Interleukin-17 / metabolism
  • Interleukin-23 / pharmacology
  • Mice
  • Molecular Dynamics Simulation
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / antagonists & inhibitors*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Protein Binding
  • Rats
  • Skin / drug effects
  • Skin / metabolism
  • Structure-Activity Relationship
  • Th17 Cells / cytology
  • Th17 Cells / drug effects
  • Th17 Cells / metabolism

Substances

  • Amides
  • Interleukin-17
  • Interleukin-23
  • Nuclear Receptor Subfamily 1, Group F, Member 3