Discovery of orally efficacious RORγt inverse agonists, part 1: Identification of novel phenylglycinamides as lead scaffolds

Bioorg Med Chem. 2018 Jan 15;26(2):483-500. doi: 10.1016/j.bmc.2017.12.006. Epub 2017 Dec 9.

Abstract

A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists were discovered through optimization of a high-throughput screen hit 1. (R)-N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methylisoxazole-5-carboxamide (22) was identified as one of the best of these compounds. It displayed higher subtype selectivity and specificity over other nuclear receptors and demonstrated in vivo potency to suppress the transcriptional activity of RORγt in a mouse PD (pharmacodynamic) model upon oral administration.

Keywords: Autoimmune disease; IL-17; Inverse agonist; Phenylglycinamide; Retinoic acid receptor-related orphan receptor-gamma t (RORγt); Th17.

MeSH terms

  • Administration, Oral
  • Animals
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Glycine / administration & dosage
  • Glycine / analogs & derivatives*
  • Glycine / chemistry
  • Glycine / pharmacology
  • Humans
  • Jurkat Cells
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Animal
  • Models, Molecular
  • Molecular Structure
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Structure-Activity Relationship

Substances

  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • phenylglycinamide
  • Glycine