Small molecule antagonist of leukocyte function associated antigen-1 (LFA-1): structure-activity relationships leading to the identification of 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)nicotinic acid (BMS-688521)

J Med Chem. 2010 May 13;53(9):3814-30. doi: 10.1021/jm100348u.

Abstract

Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target. This article will detail the structure-activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clinical compound (1), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clinical trials.

MeSH terms

  • Humans
  • Hydantoins / pharmacokinetics*
  • Hydantoins / pharmacology
  • Immunologic Factors / chemistry*
  • Lymphocyte Function-Associated Antigen-1 / chemistry
  • Lymphocyte Function-Associated Antigen-1 / drug effects*
  • Lymphocyte Function-Associated Antigen-1 / immunology
  • Nicotinic Acids / pharmacokinetics*
  • Nicotinic Acids / toxicity
  • Structure-Activity Relationship

Substances

  • Hydantoins
  • Immunologic Factors
  • Lymphocyte Function-Associated Antigen-1
  • Nicotinic Acids