title: 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).
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.
authors.affiliation: Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543, USA. scott.watterson@bms.com
authors.forename: Scott H
authors.initials: SH
authors.lastname: Watterson
authors.forename: Zili
authors.initials: Z
authors.lastname: Xiao
authors.forename: Dharmpal S
authors.initials: DS
authors.lastname: Dodd
authors.forename: David R
authors.initials: DR
authors.lastname: Tortolani
authors.forename: Wayne
authors.initials: W
authors.lastname: Vaccaro
authors.forename: Dominique
authors.initials: D
authors.lastname: Potin
authors.forename: Michele
authors.initials: M
authors.lastname: Launay
authors.forename: Dawn K
authors.initials: DK
authors.lastname: Stetsko
authors.forename: Stacey
authors.initials: S
authors.lastname: Skala
authors.forename: Patric M
authors.initials: PM
authors.lastname: Davis
authors.forename: Deborah
authors.initials: D
authors.lastname: Lee
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Yang
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
authors.forename: Praveen
authors.initials: P
authors.lastname: Balimane
authors.forename: Karishma
authors.initials: K
authors.lastname: Patel
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.forename: Pathanjali
authors.initials: P
authors.lastname: Kadiyala
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Tebben
authors.forename: Steven
authors.initials: S
authors.lastname: Sheriff
authors.forename: Chiehying Y
authors.initials: CY
authors.lastname: Chang
authors.forename: Theresa
authors.initials: T
authors.lastname: Ziemba
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhang
authors.forename: Bang-Chi
authors.initials: BC
authors.lastname: Chen
authors.forename: Albert J
authors.initials: AJ
authors.lastname: DelMonte
authors.forename: Nelly
authors.initials: N
authors.lastname: Aranibar
authors.forename: Murray
authors.initials: M
authors.lastname: McKinnon
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Suchard
authors.forename: T G
authors.initials: TG
authors.lastname: Murali Dhar
mesh_terms: D006801:Humans; D006827:Hydantoins / Q000493:pharmacokinetics* / Q000494:pharmacology; D007155:Immunologic Factors / Q000737:chemistry*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology; D009539:Nicotinic Acids / Q000493:pharmacokinetics* / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D006827:Hydantoins; D007155:Immunologic Factors; D016169:Lymphocyte Function-Associated Antigen-1; D009539:Nicotinic Acids