Tricyclic-Carbocyclic RORγt Inverse Agonists-Discovery of BMS-986313

J Med Chem. 2021 Mar 11;64(5):2714-2724. doi: 10.1021/acs.jmedchem.0c01992. Epub 2021 Feb 16.

Abstract

SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound 1 (BMS-986251) led to tricyclic-carbocyclic analogues represented by 3-7 and culminated in the identification of 3d (BMS-986313), with structural differences distinct from 1. The X-ray co-crystal structure of 3d with the ligand binding domain of RORγt revealed several key interactions, which are different from 1. The in vitro and in vivo PK profiles of 3d are described. In addition, we demonstrate robust efficacy of 3d in two preclinical models of psoriasis-the IMQ-induced skin lesion model and the IL-23-induced acanthosis model. The efficacy seen with 3d in these models is comparable to the results observed with 1.

MeSH terms

  • Amides / chemistry
  • Amides / pharmacokinetics
  • Amides / therapeutic use*
  • Animals
  • Drug Inverse Agonism
  • Female
  • Humans
  • Hydrocarbons, Cyclic / chemistry
  • Hydrocarbons, Cyclic / pharmacokinetics
  • Hydrocarbons, Cyclic / therapeutic use*
  • Interleukin-23
  • Mice
  • Mice, Inbred C57BL
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / antagonists & inhibitors*
  • Psoriasis / chemically induced
  • Psoriasis / drug therapy*
  • Rats
  • Structure-Activity Relationship

Substances

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