Abstract
Semicarbazide-sensitive amine oxidase (SSAO), also known as vascular adhesion protein-1 (VAP-1), is a member of the copper-dependent amine oxidase family that is associated with various forms of inflammation and fibrosis. To investigate the therapeutic potential of SSAO/VAP-1 inhibition, potent and selective inhibitors with drug-like properties are required. PXS-4681A [(Z)-4-(2-(aminomethyl)-3-fluoroallyloxy)benzenesulfonamide hydrochloride] is a mechanism-based inhibitor of enzyme function with a pharmacokinetic and pharmacodynamic profile that ensures complete, long-lasting inhibition of the enzyme after a single low dose in vivo. PXS-4681A irreversibly inhibits the enzyme with an apparent Ki of 37 nM and a kinact of 0.26 min(-1) with no observed turnover in vitro. It is highly selective for SSAO/VAP-1 when profiled against related amine oxidases, ion channels, and seven-transmembrane domain receptors, and is superior to previously reported inhibitors. In mouse models of lung inflammation and localized inflammation, dosing of this molecule at 2 mg/kg attenuates neutrophil migration, tumor necrosis factor-α, and interleukin-6 levels. These results demonstrate the drug-like properties of PXS-4681A and its potential use in the treatment of inflammation.
MeSH terms
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Adipose Tissue / drug effects
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Adipose Tissue / enzymology
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Allyl Compounds / chemistry
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Allyl Compounds / pharmacokinetics
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Allyl Compounds / pharmacology*
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Allyl Compounds / therapeutic use
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Amine Oxidase (Copper-Containing) / antagonists & inhibitors*
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Animals
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacokinetics
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Anti-Inflammatory Agents / pharmacology*
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Anti-Inflammatory Agents / therapeutic use
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Cell Adhesion Molecules / antagonists & inhibitors*
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Dermatitis / drug therapy
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Dermatitis / enzymology
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Dermatitis / immunology
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Disease Models, Animal
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Dogs
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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Humans
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In Vitro Techniques
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Mice
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Microsomes / drug effects
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Microsomes / enzymology
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Models, Biological
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Molecular Structure
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Pneumonia / drug therapy
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Pneumonia / enzymology
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Pneumonia / immunology
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Rabbits
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Rats
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacokinetics
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Small Molecule Libraries / pharmacology*
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Small Molecule Libraries / therapeutic use
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Species Specificity
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Sulfonamides / chemistry
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology*
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Sulfonamides / therapeutic use
Substances
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4-(2-(aminomethyl)-3-fluoroallyloxy)benzenesulfonamide
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Allyl Compounds
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Anti-Inflammatory Agents
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Cell Adhesion Molecules
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Enzyme Inhibitors
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Small Molecule Libraries
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Sulfonamides
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AOC3 protein, human
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Amine Oxidase (Copper-Containing)