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.
Scott H Watterson  1 ,  Zili Xiao ,  Dharmpal S Dodd ,  David R Tortolani ,  Wayne Vaccaro ,  Dominique Potin ,  Michele Launay ,  Dawn K Stetsko ,  Stacey Skala ,  Patric M Davis ,  Deborah Lee ,  Xiaoxia Yang ,  Kim W McIntyre ,  Praveen Balimane ,  Karishma Patel ,  Zheng Yang ,  Punit Marathe ,  Pathanjali Kadiyala ,  Andrew J Tebben ,  Steven Sheriff ,  Chiehying Y Chang ,  Theresa Ziemba ,  Huiping Zhang ,  Bang-Chi Chen ,  Albert J DelMonte ,  Nelly Aranibar ,  Murray McKinnon ,  Joel C Barrish ,  Suzanne J Suchard ,  T G Murali Dhar
Affiliations
  • 1. Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543, USA. [email protected]
PMID: 20405922 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.

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