Cutting edge: a small molecule antagonist of LFA-1-mediated cell adhesion.
LFA-1 (CD18,CD11a) is a cell-adhesion molecule that mediates critical immunological processes. In this paper we report the discovery and characterization of (R)-5-(4-bromobenzyl)-3-(3, 5-dichlorophenyl)-1,5-dimethylimidazolidine-2,4-dione (BIRT 377), an orally bioavailable small molecule that interacts specifically with LFA-1 via noncovalent binding to the CD11a chain and prevents LFA-1 from binding to its ligand, ICAM-1. BIRT 377 inhibits lymphocyte activity both in vitro and in vivo, in functional assays that require LFA-1-mediated cell adhesion. These results demonstrate that LFA-1-mediated leukocyte adhesion can be antagonized with noncharged, low m.w. molecules and suggest that the potential therapeutic value of adhesion inhibitors can be attained with a small, orally bioavailable compound.
Kelly
T A
TA
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA. tkelly@rdg.boehringer-ingelheim.com
Jeanfavre
D D
DD
McNeil
D W
DW
Woska
J R
JR
Reilly
P L
PL
Mainolfi
E A
EA
Kishimoto
K M
KM
Nabozny
G H
GH
Zinter
R
R
Bormann
B J
BJ
Rothlein
R
R
D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002449:Cell Aggregation / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D048289:Imidazolidines; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007957:Leukocyte Adherence Inhibition Test; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C400461:BIRT 377; D007093:Imidazoles; D048289:Imidazolidines; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1