SMALL MOLECULE INHIBITORS OF SSAO AS THERAPEUTICS FOR INFLAMMATORY AND AUTOIMMUNE DISORDERS

Luisa Salter-Cid, Eric Wang, Jun Zhang, Keith Cockerill, Matthew Linnik
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 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 ammonia. Membrane-bound SSAO is an 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 seem to be involved in the adhesion cascade. The fact that SSAO 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 inflammatory and autoimmune diseases. We have developed potent (IC50< 35 nM), selective, orally available inhibitors that are able to block both the enzymatic and adhesion functions of SSAO. These compounds reduce inflammation and tissue cytokine levels in rodent models of inflammatory and autoimmune disorders. Overall, the data suggest that small molecule SSAO inhibitors may be suitable for the development of potent and selective drugs for treatment of acute and chronic inflammatory diseases.

Presented at
11th Amine Oxidase Workshop Amine Oxidases: Function and Disfunction
University of St. Andrews, Scotland
July 25-29, 2004