This SSAO/VAP-1-directed anti-inflammatory agent (FW = 342.84 g/mol) is a potent and selective mechanism-based inhibitor (Ki = 37 nM; kinact = 0.26 min–1) of Semicarbazide-Sensitive Amine Oxidase (SSAO), or Vascular Adhesion Protein-1 (VAP-1), a copper-dependent amine oxidase associated with various forms of inflammation and fibrosis. SSAO/VAP-1 catalyzes the oxidation of primary amine substrates (including benzylamine, tyramine, methylamine, n-decylamine, histamine, tryptamine or b-phenylethylamine) to aldehydes, releasing ammonia and hydrogen peroxide upon regeneration of its 6-hydroxy-dopa-quinone (TPQ) co-factor. PXS-4681A is highly selective for SSAO/VAP-1, when profiled against related amine oxidases, ion channels and 7-TM receptors, superior to inhibitors reported previously. While the exact physiological role of this enzyme is presently not well understood, PXS-4681A (at 2 mg/kg) attenuates neutrophil migration, TNF-α and IL-6 levels in mouse models of lung inflammation and localized inflammation. Such findings suggest SSAO inhibition leads to decreased neutrophil rolling/extravasation, resulting in a reduction in inflammation.
