1. Academic Validation
  2. 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)

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

Affiliation

  • 1 Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543, USA. scott.watterson@bms.com
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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