De novo design, synthesis, and in vitro activity of LFA-1 antagonists based on a bicyclic[5.5]hydantoin scaffold.
LFA-1 (leukocyte function-associated antigen-1), is a member of the beta(2)-integrin family and is expressed on all leukocytes. The LFA-1/ICAM interaction promotes tight adhesion between activated leukocytes and the endothelium, as well as between T cells and antigen-presenting cells. Evidence from both animal models and clinical trials provides support for LFA-1 as a target in several different inflammatory diseases. This paper describes the de novo design, synthesis and in vitro activity of LFA-1 antagonists based on a bicyclic[5.5]hydantoin scaffold.
Potin
Dominique
D
Cerep, 128, rue Danton, 92500 Rueil-Malmaison, France.
Launay
Michele
M
Nicolai
Eric
E
Fabreguette
Maud
M
Malabre
Patrice
P
Caussade
François
F
Besse
Dominique
D
Skala
Stacey
S
Stetsko
Dawn K
DK
Todderud
Gordon
G
Beno
Brett R
BR
Cheney
Daniel L
DL
Chang
Chiehying J
CJ
Sheriff
Steven
S
Hollenbaugh
Diane L
DL
Barrish
Joel C
JC
Iwanowicz
Edwin J
EJ
Suchard
Suzanne J
SJ
Dhar
T G Murali
TG
D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis* / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000187:drug effects*; D008968:Molecular Conformation; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship
D019086:Bridged Bicyclo Compounds, Heterocyclic; D006827:Hydantoins; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1