Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist, Preclinical Candidate for the Topical Treatment of Psoriasis

ChemMedChem. 2018 Feb 20;13(4):321-337. doi: 10.1002/cmdc.201700758. Epub 2018 Feb 6.

Abstract

With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-[(tetrahydro-2H-pyran-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (CD12681), a potent inverse agonist with in vivo activity in an IL-23-induced mouse skin inflammation model.

Keywords: RORγ; interleukin 17; lipophilic ligand efficiency; psoriasis; topical application.

MeSH terms

  • Administration, Topical
  • Animals
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Drug Inverse Agonism
  • Humans
  • Inhibitory Concentration 50
  • Interleukin-17 / metabolism
  • Interleukin-23 / pharmacology
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Psoriasis / drug therapy*
  • Psoriasis / pathology
  • Skin Diseases / chemically induced
  • Skin Diseases / drug therapy
  • Skin Diseases / pathology
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*
  • Sulfonamides / metabolism
  • Sulfonamides / therapeutic use
  • Th17 Cells / cytology
  • Th17 Cells / drug effects
  • Th17 Cells / metabolism

Substances

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