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