4-Substituted-8-(1-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-one as a novel class of highly selective GlyT1 inhibitors with superior pharmacological and pharmacokinetic parameters

Bioorg Med Chem Lett. 2006 Aug 15;16(16):4321-5. doi: 10.1016/j.bmcl.2006.05.063. Epub 2006 Jun 9.

Abstract

A novel class of 4-substituted-8-(1-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-ones have been discovered and developed as potent and selective GlyT1 inhibitors. The molecules are devoid of activity at the GlyT2 isoform and display excellent selectivities against the mu opioid receptor as well as the nociceptin/orphanin FQ peptide (NOP) receptor. These molecules also exhibit superior pharmacological and pharmacokinetic parameters, relative to all GlyT1 inhibitors of the spiropiperidine family, culminating in the identification of 16b with an oral bioavailability of approximately 60%. In addition, a straightforward two-step procedure for the assembly of the target molecules is also presented.

MeSH terms

  • Administration, Oral
  • Animals
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors
  • Glycine Plasma Membrane Transport Proteins / chemistry*
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Mice
  • Microsomes
  • Models, Chemical
  • Nociceptin
  • Opioid Peptides / chemistry
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Protein Binding
  • Protein Isoforms
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Temperature

Substances

  • Ether-A-Go-Go Potassium Channels
  • Glycine Plasma Membrane Transport Proteins
  • KCNH6 protein, human
  • Opioid Peptides
  • Piperidines
  • Protein Isoforms
  • SLC6A5 protein, human
  • SLC6A9 protein, human
  • Spiro Compounds