PXS-4681A, a potent and selective mechanism-based inhibitor of SSAO/VAP-1 with anti-inflammatory effects in vivo.

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.

• Authors: Jonathan S Foot, Tin T Yow, Heidi Schilter, Alberto Buson, Mandar Deodhar, Alison D Findlay, Lily Guo, Ian A McDonald, Craig I Turner, Wenbin Zhou, Wolfgang Jarolimek
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 347 Issue 2 Pg. 365-74 (Nov 2013) ISSN: 1521-0103 [Electronic] United States
• PMID: 23943052 (Publication Type: Journal Article)

Chemical References

• 4-(2-(aminomethyl)-3-fluoroallyloxy)benzenesulfonamide
• Allyl Compounds
• Anti-Inflammatory Agents
• Cell Adhesion Molecules
• Enzyme Inhibitors
• Small Molecule Libraries
• Sulfonamides
• AOC3 protein, human
• Amine Oxidase (Copper-Containing)

Topics

• Adipose Tissue (drug effects, enzymology)
• Allyl Compounds (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Amine Oxidase (Copper-Containing) (antagonists & inhibitors)
• Animals
• Anti-Inflammatory Agents (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Cell Adhesion Molecules (antagonists & inhibitors)
• Dermatitis (drug therapy, enzymology, immunology)
• Disease Models, Animal
• Dogs
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Humans
• In Vitro Techniques
• Mice
• Microsomes (drug effects, enzymology)
• Models, Biological
• Molecular Structure
• Pneumonia (drug therapy, enzymology, immunology)
• Rabbits
• Rats
• Small Molecule Libraries (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Species Specificity
• Sulfonamides (chemistry, pharmacokinetics, pharmacology, therapeutic use)