Discovery of N-(2-hydroxy-2-aryl-cyclohexyl) substituted spiropiperidines as GlyT1 antagonists with improved pharmacological profile

Bioorg Med Chem Lett. 2006 Jan 15;16(2):354-7. doi: 10.1016/j.bmcl.2005.09.067. Epub 2005 Oct 21.

Abstract

During SAR exploration of N-(2-aryl-cyclohexyl) substituted spiropiperidine as GlyT1 inhibitors, it was found that introduction of an hydroxy group in position 2 of the cyclohexyl residue considerably improves the pharmacological profile. In particular, reduction of the binding affinity at the nociceptin/orphanin FQ peptide and the mu opioid receptors was achieved.

MeSH terms

  • Binding Sites
  • Drug Evaluation, Preclinical
  • Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Humans
  • In Vitro Techniques
  • Molecular Conformation
  • Narcotic Antagonists
  • Nociceptin Receptor
  • Piperidines* / chemistry
  • Piperidines* / classification
  • Piperidines* / pharmacology
  • Receptors, Opioid
  • Receptors, Opioid, mu / antagonists & inhibitors
  • Spiro Compounds* / chemistry
  • Spiro Compounds* / classification
  • Spiro Compounds* / pharmacology
  • Structure-Activity Relationship

Substances

  • Glycine Plasma Membrane Transport Proteins
  • Narcotic Antagonists
  • Piperidines
  • Receptors, Opioid
  • Receptors, Opioid, mu
  • SLC6A5 protein, human
  • SLC6A9 protein, human
  • Spiro Compounds
  • Nociceptin Receptor
  • OPRL1 protein, human