SMALL MOLECULE INHIBITORS OF SSAO /AOC3 AS THERAPEUTICS FOR INFLAMMATORY AND AUTOIMMUNE DISORDERS

Anne M. O’Rourke, Luisa M. Salter-Cid, Eric Wang, Andrew Miller, Hongfeng Gao, Li Huang, Arnie Garcia, Erika M. Podar, Matthew D. Linnik La Jolla Pharmaceutical Company, San Diego, CA

Abstract

Purpose. Human semicarbazide-sensitive amine oxidase (SSAO, AOC3) is a copper containing amine oxidase having both enzymatic and adhesive function, and is also known as vascular adhesion protein-1 (VAP-1). SSAO catalyzes the oxidative deamination of primary amines, forming the corresponding aldehyde and releasing H2O2 and ammonia. Membrane-bound SSAO/VAP-1 is an inflammation-inducible, endothelial cell adhesion molecule that mediates binding between leukocytes and activated endothelium in inflamed vessels. The fact that SSAO/VAP-1 is a dual-function molecule with inter-related adhesive and enzymatic functions that are upregulated under inflammatory conditions makes it a promising potential target for the development of novel therapeutics to treat inflammatory and autoimmune diseases.

Results. We have developed potent (IC 50 <35nM), selective, orally available small molecule inhibitors that are able to block both the enzymatic and adhesive functions of SSAO/VAP-1. The compounds reduce adhesion of peripheral blood mononuclear cells to endothelial cell layers, and inhibit inflammation and tissue cytokine levels in several rodent models of inflammation and autoimmune disorders. Models where SSAO inhibitions provide benefit include carrageenan-induced paw edema, collagen-induced arthritis, oxazalone-induced ulcerative colitis and relapsing experimental autoimmune encephalomyelitis. Improved clinical scores were observed in these models whether the compounds were administered in a prophylactic or therapeutic manner.

Conclusion. Collectively, the data suggest that small molecule inhibitors of SSAO may provide clinical benefit in acute and chronic inflammatory diseases by inhibiting leukocyte extravasation in inflamed tissue.

Presented at the
ACR/ARHP Scientific Meeting, San Diego, CA
November 14, 2005