Discovery and development of 5-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl-methyl]-3-thiophenecarboxylic acid (BMS-587101)--a small molecule antagonist of leukocyte function associated antigen-1.
LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.
Potin
Dominique
D
Cerep, 19 avenue du Quebec, 91951 Courtaboeuf cedex, France.
Launay
Michele
M
Monatlik
Francoise
F
Malabre
Patrice
P
Fabreguettes
Maud
M
Fouquet
Andre
A
Maillet
Magali
M
Nicolai
Eric
E
Dorgeret
Loïc
L
Chevallier
François
F
Besse
Dominique
D
Dufort
Monique
M
Caussade
François
F
Ahmad
Syed Z
SZ
Stetsko
Dawn K
DK
Skala
Stacey
S
Davis
Patricia M
PM
Balimane
Praveen
P
Patel
Karishma
K
Yang
Zheng
Z
Marathe
Punit
P
Postelneck
Jennifer
J
Townsend
Robert M
RM
Goldfarb
Valentina
V
Sheriff
Steven
S
Einspahr
Howard
H
Kish
Kevin
K
Malley
Mary F
MF
DiMarco
John D
JD
Gougoutas
Jack Z
JZ
Kadiyala
Pathanjali
P
Cheney
Daniel L
DL
Tejwani
Ravindra W
RW
Murphy
Denette K
DK
Mcintyre
Kim W
KW
Yang
Xiaoxia
X
Chao
Sam
S
Leith
Leslie
L
Xiao
Zili
Z
Mathur
Arvind
A
Chen
Bang-Chi
BC
Wu
Daugh-Rurng
DR
Traeger
Sarah C
SC
McKinnon
Murray
M
Barrish
Joel C
JC
Robl
Jeffrey A
JA
Iwanowicz
Edwin J
EJ
Suchard
Suzanne J
SJ
Dhar
T G Murali
TG
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D018360:Crystallography, X-Ray; D004285:Dogs; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011014:Pneumonia / Q000188:drug therapy / Q000276:immunology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014184:Transplantation, Homologous
C517055:5-(9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro(4,4)non-7-ylmethyl)-3-thiophenecarboxylic acid; D016169:Lymphocyte Function-Associated Antigen-1; D013141:Spiro Compounds; D013876:Thiophenes