Discovery and development of 5-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl-methyl]-3-thiophenecarboxylic acid (BMS-587101)--a small molecule antagonist of leukocyte function associated antigen-1

J Med Chem. 2006 Nov 30;49(24):6946-9. doi: 10.1021/jm0610806.

Abstract

LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.

MeSH terms

  • Animals
  • Cell Adhesion / drug effects
  • Crystallography, X-Ray
  • Dogs
  • Graft Rejection / prevention & control
  • Humans
  • Lymphocyte Function-Associated Antigen-1 / chemistry
  • Lymphocyte Function-Associated Antigen-1 / metabolism*
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Pneumonia / drug therapy
  • Pneumonia / immunology
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / pharmacokinetics
  • Spiro Compounds / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis*
  • Thiophenes / pharmacokinetics
  • Thiophenes / pharmacology
  • Transplantation, Homologous

Substances

  • 5-(9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro(4,4)non-7-ylmethyl)-3-thiophenecarboxylic acid
  • Lymphocyte Function-Associated Antigen-1
  • Spiro Compounds
  • Thiophenes

Associated data

  • PDB/2ICA