BENEFIT OF INHIBITING SSA0 IN INFLAMMATORY NEUROLOGICAL DISORDERS

Anne M. O’Rourke, Dale Pelligrino, Eric Y. Wang, Luisa Salter-Cid, Li Huang, Andrew Miller, Erika M. Podar, Mary MacDonald, David S. Jones and Matthew D. Linnik,La Jolla Pharmaceutical Co, San Diego CA and University of Illinois at Chicago (DP)

Abstract

Human semicarbazide sensitive amine oxidase (SSAO, AOC3, EC 1.4.3.6, VAP-1) has interdependent enzymatic and adhesive functions. SSAO expression on the luminal surface of endothelial cells is upregulated at sites of inflammation, and plays a role in trafficking of leukocytes to the inflammatory foci. We have developed series of potent, specific and orally available small molecule SSAO inhibitors that block both the enzymatic and adhesive functions of the enzyme. When administered either in prophylactic or therapeutic fashions, the inhibitors display efficacy in rodent models of acute inflammation, as well as in inflammatory bowel disease and arthritis. Here we provide evidence that inhibition of SSAO leads to striking improvement in rodent models of two neurological disorders, stroke and multiple sclerosis.

Inhibition of SSAO attenuates leukocyte adhesion and completely ablates cell infiltration via pial veins after transient forebrain ischemia in diabetic ovariectomized rats given estrogen replacement therapy. This inhibition was apparent at 2 – 10 hours of reperfusion and was associated with marked improvement of histopathology and neurological function at 72 hours of reperfusion.

In a mouse model of multiple sclerosis, relapsing-remitting experimental autoimmune encephalomyelitis, prophylactic administration of SSAO inhibitors significantly decreased both the incidence of disease and the clinical score. Moreover, such improvement was also observed when SSAO inhibitors were given at peak of disease, or during remission. Current lead compounds are highly specific, have low nanomolar IC50s for human SSAO, show efficacy in animal models of acute and chronic inflammation, and have favorable ADMET profiles. In summary, the data suggest that small molecule SSAO inhibitors may provide clinical benefit in neurologic disorders by impeding the trafficking of leukocytes to sites of inflammation.

Presented at the
12th Amine Oxidase & Trace Amines Workshop
Rotterdam, the Netherlands
August 2, 2006