Selective cell adhesion inhibitors: Barbituric acid based alpha4beta7--MAdCAM inhibitors

Geraldine C Harriman; Matthias Brewer; Robert Bennett; Cyrille Kuhn; Marc Bazin; Greg Larosa; Paul Skerker; Nancy Cochran; Debra Gallant; Deborah Baxter; Dominic Picarella; Bruce Jaffee; Jay R Luly; Michael J Briskin

doi:10.1016/j.bmcl.2007.07.068

Selective cell adhesion inhibitors: Barbituric acid based alpha4beta7--MAdCAM inhibitors

Bioorg Med Chem Lett. 2008 Apr 1;18(7):2509-12. doi: 10.1016/j.bmcl.2007.07.068. Epub 2007 Aug 21.

Authors

Geraldine C Harriman¹, Matthias Brewer, Robert Bennett, Cyrille Kuhn, Marc Bazin, Greg Larosa, Paul Skerker, Nancy Cochran, Debra Gallant, Deborah Baxter, Dominic Picarella, Bruce Jaffee, Jay R Luly, Michael J Briskin

Affiliation

¹ Millennium Pharmaceuticals, 35 Landsdowne Street, Cambridge, MA 02139, USA. gharriman@galenea.com

PMID: 18331794
DOI: 10.1016/j.bmcl.2007.07.068

Abstract

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.

Publication types

Comparative Study

MeSH terms

Animals
Barbiturates / chemical synthesis
Barbiturates / pharmacology*
Binding Sites
Cell Adhesion / drug effects*
Cell Adhesion / physiology
Cell Adhesion Molecules
Immunoglobulins / metabolism
Integrin alpha4beta1 / metabolism
Integrins / antagonists & inhibitors*
Integrins / metabolism
Mice
Models, Chemical
Mucoproteins / antagonists & inhibitors*
Mucoproteins / metabolism
Structure-Activity Relationship
Vascular Cell Adhesion Molecule-1 / metabolism

Substances

Barbiturates
Cell Adhesion Molecules
Immunoglobulins
Integrin alpha4beta1
Integrins
MADCAM1 protein, human
Mucoproteins
Vascular Cell Adhesion Molecule-1
integrin alpha4beta7
barbituric acid