The discovery and development of selective 3-fluoro-4-aryloxyallylamine inhibitors of the amine oxidase activity of semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1)

Bioorg Med Chem Lett. 2012 Jun 15;22(12):3935-40. doi: 10.1016/j.bmcl.2012.04.111. Epub 2012 Apr 30.

Abstract

A new class of 3-fluoroallyl amine-based SSAO/VAP-1 inhibitors is reported. These compounds have excellent selectivity over diamine oxidase, MAO-A and MAO-B. Synthesis and SAR studies leading to compound 28 (PXS-4159A) are reported. The pharmacokinetic profile of 28 in the rat, together with activity in a murine model of lung inflammation are also disclosed.

MeSH terms

  • Allyl Compounds / chemical synthesis*
  • Allyl Compounds / pharmacokinetics
  • Allyl Compounds / pharmacology
  • Amine Oxidase (Copper-Containing) / antagonists & inhibitors*
  • Amine Oxidase (Copper-Containing) / metabolism
  • Amines / chemical synthesis*
  • Amines / pharmacokinetics
  • Amines / pharmacology
  • Animals
  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / pharmacology
  • Drug Discovery
  • Halogenation
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Mice
  • Models, Molecular
  • Monoamine Oxidase Inhibitors / chemical synthesis*
  • Monoamine Oxidase Inhibitors / pharmacokinetics
  • Monoamine Oxidase Inhibitors / pharmacology
  • Pneumonia / drug therapy*
  • Pneumonia / enzymology
  • Rats
  • Structure-Activity Relationship

Substances

  • Allyl Compounds
  • Amines
  • Anti-Inflammatory Agents
  • Isoenzymes
  • Monoamine Oxidase Inhibitors
  • Amine Oxidase (Copper-Containing)