La Jolla hails SSAO inhibitor potential
novel, orally active small molecule inhibitors of a central enzyme
may provide clinical benefit for the treatment of stroke,
ulcerative colitis, and other autoimmune diseases and inflammatory
disorders.
The pharmaceuticals firm is championing the potential of semicarbazide-sensitive amine oxidase (SSAO) inhibitors, also known as vascular adhesion protein-1 or VAP-1, a dual-function molecule with enzymatic and adhesion activities.
SSAO contributes to the adhesion of white blood cells to endothelial cells and is greatly amplified in blood vessels at sites of inflammation. The enzyme activity also produces molecules that can exacerbate inflammation.
Increases in the levels of plasma or membrane-associated SSAO have been reported for many inflammation-associated diseases including rheumatoid arthritis, inflammatory bowel disease, diabetes, atherosclerosis, and chronic heart failure.
Semicarbazide-sensitive amine oxidase (SSAO) belongs to a ubiquitous family of copper-containing amine oxidases (CuAOs). SSAO is also known as vascular adhesion protein-1 (VAP-1) and has been identified as one of the adhesion molecules involved in the leukocyte-extravasation process.
In preclinical studies conducted by Company scientists, SSAO inhibitors blocked both the enzymatic and adhesion functions of SSAO and were shown in animal models to be potent inhibitors of disease activity.
The first paper, published in the Journal of Pharmacology and Experimental Therapeutics on December 8, 2005 by Xu et al, indicated that a selective SSAO inhibitor, LJP 1207, could provide clinical benefit in the treatment of stroke.
Data published in this paper demonstrated that treatment in an animal model with LJP 1207 resulted in marked reduction in the adhesion and infiltration of white blood cells into the blood vessels of the brain after the occurrence of stroke and significantly less neurological damage.
"Our findings with La Jolla's inhibitor of SSAO/VAP-1 in stroke are particularly exciting," said Dale Pelligrino, Professor and Director, Neuroanesthesia Research Laboratory, University of Illinois at Chicago.
"Treatment with LJP 1207 as late as six hours after the onset of stroke in an animal model still had a positive protective effect of reducing inflammation and neurological damage."
The second paper, by Salter-Cid et al, was published in the Journal of Pharmacology and Experimental Therapeutics, volume 315, pages 553-562, 2005, providing further evidence of the potential of LJP 1207 to both acute and chronic inflammation.
In a mouse model of chronic inflammation resulting in ulcerative colitis, treatment with LJP 1207 significantly reduced mortality and loss of body weight, as well as colon injury and ulceration.
In a model of acute inflammation, treatment with LJP 1207 given either before or after inflammation was induced, resulted in the marked inhibition of both swelling and inflammation.
"These two papers highlight the impact of treatment with SSAO inhibitors on disease models of stroke, ulcerative colitis and general inflammation. The efficacy of our lead compounds has also been demonstrated in animal models of multiple sclerosis and rheumatoid arthritis," said Linnik.
"Although stroke is a leading cause of death and disability, there has been a lack of success in developing drug candidates to treat stroke. We are excited about the potential to provide a novel oral anti-inflammatory therapy for the treatment of a spectrum of diseases that are caused or worsened by inflammation."
