Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 2. Discovery of 7-azaspiro[3.5]nonane urea PF-04862853, an orally efficacious inhibitor of fatty acid amide hydrolase (FAAH) for pain

Bioorg Med Chem Lett. 2011 Nov 1;21(21):6545-53. doi: 10.1016/j.bmcl.2011.08.048. Epub 2011 Aug 19.


Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate.

MeSH terms

  • Administration, Oral
  • Amidohydrolases / antagonists & inhibitors*
  • Analgesics / administration & dosage
  • Analgesics / chemistry
  • Analgesics / pharmacology*
  • Analgesics / therapeutic use
  • Animals
  • Aza Compounds / administration & dosage
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology
  • Aza Compounds / therapeutic use
  • Biological Availability
  • Chromatography, High Pressure Liquid
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Pain / drug therapy*
  • Rats
  • Spiro Compounds / administration & dosage
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Spiro Compounds / therapeutic use


  • Analgesics
  • Aza Compounds
  • Enzyme Inhibitors
  • PF-04862853
  • Spiro Compounds
  • Amidohydrolases
  • fatty-acid amide hydrolase