Anti-inflammatory effects of inhibiting the amine oxidase activity of semicarbazide-sensitive amine oxidase.
Human semicarbazide-sensitive amine oxidase (SSAO) or vascular adhesion protein-1 (VAP-1) is a copper-containing amine oxidase (AOC3, EC 1.4.3.6) that has both enzymatic and adhesive function. SSAO catalyzes the oxidative deamination of primary amines, resulting in the formation of the corresponding aldehyde and release of hydrogen peroxide and ammonia. Membrane-bound SSAO is an inflammation-inducible endothelial cell adhesion molecule that mediates the interaction between leukocytes and activated endothelial cells in inflamed vessels. Both the direct adhesive and enzymatic functions seem to be involved in the adhesion cascade. LJP 1207 [N'-(2-phenyl-allyl)-hydrazine hydrochloride] is a potent (human SSAO IC(50) = 17 nM), selective, and orally available SSAO inhibitor that blocks both the enzymatic and adhesion functions of SSAO/VAP-1. In a mouse model of ulcerative colitis, LJP 1207 significantly reduces mortality, loss of body weight, and colonic cytokine levels. Quantitative histopathological assessment of colitis activity in this model showed a highly significant suppression of inflammation, injury, and ulceration scores in the animals treated with the SSAO/VAP-1 inhibitor. LJP 1207 also reduced serum levels of tumor necrosis factor-alpha and interleukin 6 in lipopolysaccharide (LPS)-challenged mice and prolonged survival post-LPS-induced endotoxemia. Therapeutic and prophylactic administration of LJP 1207 in the rat carrageenan footpad model also markedly inhibited swelling and inflammation. Overall, the data suggest that small molecule SSAO/VAP-1 inhibitors may provide clinical benefit in the treatment of acute and chronic inflammatory diseases.
Salter-Cid
Luisa M
LM
La Jolla Pharmaceutical Company, San Diego, CA 92121, USA.
Wang
Eric
E
O'Rourke
Anne M
AM
Miller
Andrew
A
Gao
Hongfeng
H
Huang
Li
L
Garcia
Arnie
A
Linnik
Matthew D
MD
D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D000893:Anti-Inflammatory Agents; D002351:Carrageenan; D002448:Cell Adhesion / Q000187:drug effects; D003001:Cloning, Molecular; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D042783:Endothelial Cells / Q000187:drug effects; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D006834:Hydrazines / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010081:Oxazolone; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D006834:Hydrazines; D008996:Monoamine Oxidase Inhibitors; C506836:N'-(2-phenylallyl)hydrazine; D010081:Oxazolone; D002351:Carrageenan; D051546:Cyclooxygenase 2; D006631:Amine Oxidase (Copper-Containing)