Design of LFA-1 antagonists based on a 2,3-dihydro-1H-pyrrolizin-5(7aH)-one scaffold.
A new class of lymphocyte function-associated antigen-1 (LFA-1) antagonists is described. Elaboration of the 2,3-dihydro-1H-pyrrolizin-5(7aH)-one scaffold resulted in the synthesis of potent inhibitors of the LFA-1/ICAM-1 interaction. Along with the in vitro activity, we present the X-ray crystal structure of the complex of compound 9b, in a novel binding mode to the I-domain of LFA-1.
Dodd
Dharmpal S
DS
Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543-4000, USA. dharmpal.dodd@bms.com
Sheriff
Steven
S
Chang
ChiehYing J
CJ
Stetsko
Dawn K
DK
Phillips
Linda M
LM
Zhang
Yingru
Y
Launay
Michele
M
Potin
Dominique
D
Vaccaro
Wayne
W
Poss
Michael A
MA
McKinnon
Murray
M
Barrish
Joel C
JC
Suchard
Suzanne J
SJ
Murali Dhar
T G
TG
D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry*; D008956:Models, Chemical; D008968:Molecular Conformation; D011758:Pyrroles / Q000737:chemistry*; D013237:Stereoisomerism; D013696:Temperature; D014965:X-Rays
D016169:Lymphocyte Function-Associated Antigen-1; D011758:Pyrroles