Discovery and evaluation of potent, tyrosine-based alpha4beta1 integrin antagonists.
Using disulphide cysteine-based inhibitors as lead structures, this communication describes our strategy for identifying more stable, potent antagonists of the alpha4beta1 integrin. These studies ultimately discovered potent, low molecular weight inhibitors based on D-thioproline-L-tyrosine.
Archibald
S C
SC
Celltech Chiroscience, Slough, UK.
Head
J C
JC
Gozzard
N
N
Howat
D W
DW
Parton
T A
TA
Porter
J R
JR
Robinson
M K
MK
Shock
A
A
Warrellow
G J
GJ
Abraham
W M
WM
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000188:drug therapy; D006207:Half-Life; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors*; D016209:Interleukin-8 / Q000494:pharmacology; D016210:Methacholine Chloride / Q000494:pharmacology; D010277:Parasympathomimetics / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors*; D012756:Sheep; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D039041:Integrin alpha4beta1; D016023:Integrins; D016209:Interleukin-8; D010277:Parasympathomimetics; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; D016210:Methacholine Chloride; D014443:Tyrosine