Selective cell adhesion inhibitors: Barbituric acid based alpha4beta7--MAdCAM inhibitors.
A novel series of barbituric acid derivatives were identified as selective inhibitors of alpha4beta7 MAdCAM (mucosal addressin cell adhesion molecule-1) interactions via a high throughput screening exercise. These inhibitors were optimized to submicromolar potencies in whole cell adhesion assays, retaining their selectivity over alpha4beta1 VCAM.
Harriman
Geraldine C
GC
Millennium Pharmaceuticals, 35 Landsdowne Street, Cambridge, MA 02139, USA. gharriman@galenea.com
Brewer
Matthias
M
Bennett
Robert
R
Kuhn
Cyrille
C
Bazin
Marc
M
Larosa
Greg
G
Skerker
Paul
P
Cochran
Nancy
N
Gallant
Debra
D
Baxter
Deborah
D
Picarella
Dominic
D
Jaffee
Bruce
B
Luly
Jay R
JR
Briskin
Michael J
MJ
D000818:Animals; D001463:Barbiturates / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D002448:Cell Adhesion / Q000187:drug effects* / Q000502:physiology; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins / Q000378:metabolism; D039041:Integrin alpha4beta1 / Q000378:metabolism; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008956:Models, Chemical; D009088:Mucoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D001463:Barbiturates; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D039041:Integrin alpha4beta1; D016023:Integrins; C504265:MADCAM1 protein, human; D009088:Mucoproteins; D019010:Vascular Cell Adhesion Molecule-1; C071777:integrin alpha4beta7; C032232:barbituric acid