Novel glycine amides, semicarbazides and fluoroallylamines as inhibitors of the amine oxidase vascular adhesion protein-1 (VAP-1)

Abstract

Vascular adhesion protein-1 (VAP-1), also known as copper-containing amine oxidase 3 (AOC3), is an enzyme implicated in the pathogenesis of various diseases. Increasing evidence highlights VAP-1 as a promising therapeutic target, particularly for the treatment of inflammatory disorders and diabetic complications. We have synthesised a series of compounds in which a heterocycle or a benzene-fused heterocycle is connected via a hydrocarbon spacer to a glycine amide, semicarbazide, or fluoroallylamine moiety. These functional groups are believed to act as reactive “warheads”, forming covalent bonds with the topaquinone cofactor at the enzyme's active site. Screening was initially conducted using bovine plasma amine oxidase (AOC4), an enzyme structurally closely related to VAP-1 (AOC3) and also referred to as secretory VAP-1 (sVAP-1). Selected compounds were subsequently evaluated for their ability to inhibit VAP-1 activity in human plasma. The results showed that glycine amide and semicarbazide analogs generally exhibited stronger inhibition of the bovine AOC4 than of the human AOC3. In contrast, fluoroallylamines displayed comparable or even greater inhibitory potency toward the human enzyme. Overall, fluoroallylamines with nanomolar IC₅₀ values were identified as the most potent inhibitors of human VAP-1, whereas glycine amides, which act as substrate inhibitors, were the least effective. In assays evaluating inhibition of the related enzyme diamine oxidase (AOC1) as well as monoamine oxidases A and B (MAO A and MAO B), the glycine amides displayed relatively high selectivity for human VAP-1. The semicarbazides, however, also showed strong inhibitory activity against AOC1. Several of the fluorinated allylamines tested were identified as highly potent, well-balanced dual inhibitors of human VAP-1 and MAO B, with (Z)-2-({3-[(1H-benzotriazol-1-yl)methyl]phenoxy}methyl)-3-fluoroprop-2-en-1-amine (94) being the most effective. Compounds with this dual inhibitory profile are thought to exert particularly beneficial effects in the treatment of inflammatory conditions.