Discovery of 6-Oxo-4-phenyl-hexanoic acid derivatives as RORγt inverse agonists showing favorable ADME profile

Bioorg Med Chem Lett. 2021 Mar 15:36:127786. doi: 10.1016/j.bmcl.2021.127786. Epub 2021 Jan 23.

Abstract

The retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt), which is a promising therapeutic target for immune diseases, is a major transcription factor of genes related to psoriasis pathogenesis, such as interleukin (IL)-17A, IL-22, and IL-23R. Inspired by the co-crystal structure of RORγt, a 6-oxo-4-phenyl-hexanoic acid derivative 6a was designed, synthesized, and identified as a ligand of RORγt. The structure-activity relationship (SAR) studies in 6a, which focus on the improvement of its membrane permeability profile by introducing chlorine atoms, led to finding 12a, which has a potent RORγt inhibitory activity and a favorable pharmacokinetic profile.

Keywords: Inverse agonist; Nuclear receptor; RORγt.

MeSH terms

  • Animals
  • Caproates / chemistry
  • Caproates / metabolism
  • Caproates / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Mice
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Structure-Activity Relationship

Substances

  • Caproates
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • hexanoic acid