Discovery, synthesis, selectivity modulation and DMPK characterization of 5-azaspiro[2.4]heptanes as potent orexin receptor antagonists

Bioorg Med Chem Lett. 2013 May 1;23(9):2653-8. doi: 10.1016/j.bmcl.2013.02.093. Epub 2013 Mar 1.

Abstract

Starting from a orexin 1 receptor selective antagonist 4,4-disubstituted piperidine series a novel potent 5-azaspiro[2.4]heptane dual orexin 1 and orexin 2 receptor antagonist class has been discovered. SAR and Pharmacokinetic optimization of this series is herein disclosed. Lead compound 15 exhibits potent activity against orexin 1 and orexin 2 receptors along with low cytochrome P450 inhibition potential, good brain penetration and oral bioavailability in rats.

MeSH terms

  • Animals
  • Aza Compounds / chemistry*
  • Biological Availability
  • Brain / drug effects
  • Brain / metabolism
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Evaluation, Preclinical
  • Half-Life
  • Heptanes / chemical synthesis
  • Heptanes / chemistry*
  • Heptanes / pharmacokinetics
  • Orexin Receptors
  • Rats
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Receptors, Neuropeptide / metabolism
  • Spiro Compounds / chemistry*
  • Structure-Activity Relationship

Substances

  • Aza Compounds
  • Cytochrome P-450 Enzyme Inhibitors
  • Heptanes
  • Orexin Receptors
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Spiro Compounds
  • Cytochrome P-450 Enzyme System