Synthesis and evaluation of paracetamol esters as novel fatty acid amide hydrolase inhibitors

J Med Chem. 2010 Mar 11;53(5):2286-98. doi: 10.1021/jm901891p.

Abstract

Fatty acid amide hydrolase (FAAH) is the key hydrolytic enzyme for the endogenous cannabinoid receptor ligand anandamide. The synthesis and evaluation for their FAAH inhibitory activities of a series of 18 paracetamol esters are described. Structure-activity relationship studies indicated that the ester (33) with a 2-(4-(2-(trifluoromethyl)pyridin-4-ylamino)phenyl)acetic acid substituent was the most potent analogue in this series. The compound inhibited FAAH activity in a competitive manner with a K(i) value of 0.16 microM. The compound was also able to inhibit the FAAH activity in rat basophilic leukemia cells as assessed by measuring either the hydrolysis of anandamide, the FAAH-dependent cellular accumulation of anandamide, or the FAAH-dependent recycling of tritium to the cell membranes. The compound also inhibited the activity of monoacylglycerol lipase (MGL), the enzyme responsible for the hydrolysis of the endogenous cannabinoid receptor ligand 2-arachidonoylglycerol, with an IC(50) value of 1.9 microM. It is concluded that the compound may be a useful template for the design of potent novel inhibitors of FAAH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Amidohydrolases / metabolism*
  • Analgesics / chemical synthesis*
  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Arachidonic Acids / metabolism
  • Benzoates / chemical synthesis*
  • Benzoates / chemistry
  • Benzoates / pharmacology
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Endocannabinoids
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Inhibitory Concentration 50
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Polyunsaturated Alkamides / metabolism
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Spectrophotometry, Infrared
  • Structure-Activity Relationship

Substances

  • Analgesics
  • Anti-Inflammatory Agents, Non-Steroidal
  • Arachidonic Acids
  • Benzoates
  • Endocannabinoids
  • Enzyme Inhibitors
  • Polyunsaturated Alkamides
  • Pyridines
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • anandamide