SMALL MOLECULE INHIBITORS OF SSAO/VAP-1 FOR THE TREATMENT OF ACUTE AND CHRONIC INFLAMMATION

Jun Zhang, Eric Wang, Matthew D. Linnik, Luisa Salter-Cid,
La Jolla Pharmaceutical Company, San Diego, CA.

Human semicarbazide-sensitive amine oxidase (SSAO) is a copper-containing amine oxidase that has both enzymatic and adhesive function, and is thus also known as vascular adhesion protein-1 (VAP-1). Most SSAOs are soluble enzymes that catalyze oxidative deamination of primary amines. The reaction results in the formation of the corresponding aldehyde and release of H2O2 and ammonium. VAP-1 is a cell-associated, inflammation-inducible, endothelial cell adhesion molecule that mediates the interaction between leukocytes and activated endothelial cells in inflamed vessels. Both the direct adhesive and enzymatic functions of SSAO/VAP-1 seem to be involved in the adhesion cascade. The fact that SSAO/VAP-1 is a dual-function molecule with interrelated enzymatic and adhesion activities that are upregulated in many inflammatory conditions makes it a promising potential target for the development of novel therapeutics to treat both acute and chronic inflammatory diseases. We have developed potent (IC50 < 35 nM), selective, orally active inhibitors that are able to block both the enzymatic and adhesion functions of SSAO/VAP-1. These compounds reduce inflammation and tissue cytokines levels in several rodent models of inflammation including carrageenan-induced paw edema in rats, collagen antibody-mediated arthritis and experimental autoimmune encephalomyelitis in mice. Overall the data suggest that small molecule SSAO/VAP-1 inhibitors may be suitable for the development of a potent and selective drug for treatment of acute and chronic inflammatory diseases such as rheumatoid arthritis and multiple sclerosis.

Presented at
Experimental Biology 2004
Washington, DC
April 17-21, 2004