Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 1: identification of 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane as lead scaffolds

Bioorg Med Chem Lett. 2011 Nov 1;21(21):6538-44. doi: 10.1016/j.bmcl.2011.08.055. Epub 2011 Aug 22.

Abstract

Herein we report the identification of two new fatty acid amide hydrolase (FAAH) inhibitor lead series with FAAH k(inact)/K(i) potency values greater than 1500M(-1)s(-1). The two novel spirocyclic cores, 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane, clearly distinguished themselves from the other spirocyclic cores on the basis of their superior potency for FAAH. Lead compounds from these two series have suitable FAAH potency and selectivity for additional medicinal chemistry optimization.

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology*
  • Drug Discovery*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • 1-oxa-8-azaspiro(4.5)decane
  • 7-azaspiro(3.5)nonane
  • Aza Compounds
  • Enzyme Inhibitors
  • Spiro Compounds
  • Amidohydrolases
  • fatty-acid amide hydrolase