Alkylamino derivatives of 4-aminomethylpyridine as inhibitors of copper-containing amine oxidases

J Med Chem. 2005 Feb 10;48(3):664-70. doi: 10.1021/jm0408316.

Abstract

The first substratelike, reversible inhibitors of different copper amine oxidases (CAOs) with IC50 (M) as low as 2.0 x 10(-8) corresponding to derivatives of 4-aminomethylpyridine with alkoxy (1a-d), alkylthio (2a,b), and alkylamino (3a-e, 4a-j) groups in the positions 3 and 5 have been prepared and studied. The inhibitors 1a-d are active on benzylamine oxidase and semicarbazide-sensitive amine oxidase and are very selective with respect to diamine oxidase, lysyl oxidase, and monoamine oxidases. The inhibitors 2a,b are selective for benzylamine oxidase whereas 2a is also a new type of good substrate of diamine oxidase. The inhibitors 3a-e and 4a-j are substratelike, reversible, nonselective inhibitors of various CAOs including pea seedling amine oxidase and Hansenula polymorpha amine oxidase, whose enzymatic sites are known from X-ray structure determinations. The inhibitors 3b,c and 4b,c are excellent substratelike tools for studies correlating CAOs that afford crystals suitable for X-ray structure determinations with CAOs from mammals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amine Oxidase (Copper-Containing) / antagonists & inhibitors*
  • Amine Oxidase (Copper-Containing) / chemistry
  • Animals
  • Kinetics
  • Lethal Dose 50
  • Mice
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / toxicity
  • Structure-Activity Relationship
  • Toxicity Tests, Acute

Substances

  • Pyridines
  • Amine Oxidase (Copper-Containing)