Dehydrophenylalanine derivatives as VLA-4 integrin antagonists.
We describe a series of dehydrophenylalanine derivatives where the Z isomers are potent VLA-4 antagonists but are subject to rapid biliary clearance and the E isomers have poor activity but have a slower rate of clearance. These configurationally constrained molecules have led to the design of a novel class of benzodiazepine VLA-4 antagonists.
Porter
John R
JR
Department of Medicinal Chemistry, Celltech R&D Ltd, 216 Bath Road, Slough SL1 4EN, UK. john.porter@celltechgroup.com
Archibald
Sarah C
SC
Brown
Julien A
JA
Childs
Kirstie
K
Critchley
David
D
Head
John C
JC
Parton
Ted A H
TA
Robinson
Martyn K
MK
Shock
Anthony
A
Taylor
Richard J
RJ
Warrellow
Graham J
GJ
D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology; D001659:Biliary Tract / Q000378:metabolism; D015195:Drug Design; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D007536:Isomerism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D039041:Integrin alpha4beta1; D001569:Benzodiazepines; D010649:Phenylalanine; C018632:phenyldehydroalanine