SMALL MOLECULE INHIBITORS OF SSAO/AOC3 FOR THERAPY OF INFLAMMATORY DISEASES

Anne M. O’Rourke, Andrew Miller, Erika Podar, Kelly Scheyhing, Li Huang, David Jones, Mary MacDonald, Huong-Thu Ton-Nu, Eric Y. Wang, Matthew D. Linnik La Jolla Pharmaceutical Co, San Diego CA

Abstract

Purpose. Semicarbazide-sensitive amine oxidase (SSAO, AOC3, also described as vascular adhesion protein-1 or VAP-1) is a copper-containing enzyme that catalyzes the oxidative deamination of primary amines to yield bioreactive products, including hydrogen peroxide, ammonia and the corresponding aldehyde. SSAO/AOC3 is a dual-function molecule having inter-dependent enzymatic and adhesive functions, and is upregulated under inflammatory conditions. The purpose of the present study was to develop potent, specific SSAO inhibitors and evaluate their potential benefit in acute inflammation and rheumatic disease models using prophylactic and therapeutic dosing regimens.

Methods.We discovered a compound designated as LJP 1586 that is potent (IC50 18 nM human SSAO), specific (tested against 25 receptors and 40 enzymes), and orally active with a favorable ADMET profile. It is a small molecule inhibitor with a formula weight of ~ 230. The compound was evaluated in rodent models of acute inflammation and arthritis

Results.In vivo experiments demonstrated both prophylactic and therapeutic efficacy of LJP 1586 in the rat paw edema model of acute inflammation and efficacy of LJP 1586 was shown to be comparable to that of indomethacin. In a murine anti-collagen antibody-induced arthritis model, dosing between days 1 and 10 with LJP 1586 or methotrexate improved clinical scores relative to vehicle control dosed animals. LJP 1586 displayed similar efficacy to methotrexate in this model. The arthritis clinical score was also reduced by LJP 1586 when dosing was delayed until after the onset of disease. In a carrageenan-elicited air pouch model, LJP 1586 inhibited trafficking of neutrophils to a similar extent as did an anti-integrin antibody.

Conclusion.LJP 1586 reduced inflammation and improved outcome in rodent models of acute inflammation and arthritis, presumably by inhibiting leukocyte extravasation into inflamed tissues. Inhibition of SSAO/AOC3 may represent a novel approach for the treatment of inflammatory disorders. This target can be effectively inhibited by an oral administered small molecule approach.

Presented at the
ACR Scientific Meeting, Washington, DC
November 14th, 2006