Inhibitors of vascular cell adhesion molecule-1 expression

Abstract

Leukocyte extravasation, a complex multistep process involving the selective recruitment of white blood cell subpopulations to specific tissues, is finely regulated to a large extent by inducible adhesion molecules on the endothelium. Secreted mediators such as tumour necrosis factor alpha (TNF-α) transcriptionally activate endothelial cells at sites of injury or inflammation, resulting in the localised de novo synthesis of cell surface proteins such as vascular cell adhesion molecule-1 (VCAM-1). Circulating leukocytes bearing the VCAM1 ligand, namely the integrin very late antigen4 (VLA-4), then bind to their corresponding adhesion receptor that is newly expressed on the luminal surface of postcapillary venules. Preclinical data strongly suggest that the VCAM-1/VLA-4 adhesion pathway significantly contributes to the pathogenesis of numerous diseases including asthma, atherosclerosis, inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis. VCAM-1 thus represents an attractive target for drug intervention due to its central role in sequential events leading to the transendothelial migration of leukocytes (e.g., T and B lymphocytes, eosinophils, monocytes). This article focuses on patents claiming inhibition of VCAM-1 gene and protein expression, primarily covering antioxidants, antisense oligonucleotides, cyclic depsipeptides of the HUN-7293 type and small heterocyclic compounds.

• α4ß1 integrin
• adhesion molecules
• antioxidants
• antisense oligonucleotides
• HUN-7293
• inhibitor
• vascular cell adhesion molecule-1 (VCAM1)
• very late antigen-4 (VLA4)