Abstract
Semicarbazide-sensitive amine oxidase (SSAO, amine oxidase, copper-containing 3, and vascular adhesion protein-1) is a copper-containing enzyme that catalyzes the oxidative deamination of primary amines to an aldehyde, ammonia, and hydrogen peroxide. SSAO is also involved in leukocyte migration to sites of inflammation, and the enzymatic activity of SSAO is essential to this role. Thus, inhibition of SSAO enzyme activity represents a target for the development of small molecule anti-inflammatory compounds. Here, we have characterized the novel SSAO inhibitor, Z-3-fluoro-2-(4-methoxybenzyl)allylamine hydrochloride (LJP 1586), and assessed its anti-inflammatory activity. LJP 1586 is a potent inhibitor of rodent and human SSAO activity, with IC50 values between 4 and 43 nM. The selectivity of LJP 1586 was confirmed with a broad panel of receptors and enzymes that included the monoamine oxidases A and B. Oral administration of LJP 1586 resulted in complete inhibition of rat lung SSAO, with an ED50 between 0.1 and 1 mg/kg, and a pharmacodynamic half-life of greater than 24 h. In a mouse model of inflammatory leukocyte trafficking oral dosing with LJP 1586 resulted in significant dose-dependent inhibition of neutrophil accumulation, with an effect comparable to that of anti-leukocyte function-associated antigen-1 antibody. In a rat model of LPS-induced lung inflammation, administration of 10 mg/kg LJP 1586 resulted in a 55% significant reduction in transmigrated cells recovered by bronchoalveolar lavage. The results demonstrate that a selective, orally active small molecule inhibitor of SSAO is an effective anti-inflammatory compound in vivo and provide further support for SSAO as a therapeutic anti-inflammatory target.
Footnotes
-
Parts of this article were previously presented in poster form: O'Rourke A, Miller A, Podar E, Scheyhing K, Huang L, Jones D, MacDonald M, Ton-Nu H, Wang E, and Linnik M (2006) Small molecule inhibitors of SSAO/AOC3 for therapy of inflammatory diseases, in Annual Meeting of the American College of Rheumatology; 2006 Nov 10–15; San Diego, CA. American College of Rheumatology, Atlanta, GA.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.107.131672.
-
ABBREVIATIONS: SSAO, semicarbazide-sensitive amine oxidase; VAP-1, vascular adhesion protein-1; LPS, lipopolysaccharide; MAO, monoamine oxidase; DAO, diamine oxidase; ANOVA, analysis of variance; COX; cyclooxygenase; LJP 1586, Z-3-fluoro-2-(4-methoxybenzyl)allylamine hydrochloride; TPQ, topaquinone; LJP 1207, N′(2-phenyl-allyl)-hydrazine hydrochloride; CHO, Chinese hamster ovary; BAL, bronchoalveolar lavage; PBS, phosphate-buffered saline; PK, pharmacokinetics; UC, umbilical cord(s); AOC, amine oxidase, copper-containing; FAD, flavin adenine dinucleotide; LFA, leukocyte function-associated antigen.
- Received September 13, 2007.
- Accepted November 8, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|