Identification of MK-1925: a selective, orally active and brain-penetrable opioid receptor-like 1 (ORL1) antagonist

Bioorg Med Chem Lett. 2009 Aug 15;19(16):4729-32. doi: 10.1016/j.bmcl.2009.06.051. Epub 2009 Jun 17.

Abstract

Structure-activity relationship studies directed toward improving the metabolic stability of compound 1 resulted in the identification of 3-[5-(3,5-difluorophenyl)-3-({[(1S,3R)-3-fluorocyclopentyl]amino}methyl)-4-methyl-1H-pyrazol-1-yl]propanenitrile 39 (MK-1925) as a selective, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonist. The compound also showed in vivo efficacy after oral dosing. Therefore, compound 39 was selected to undergo further studies as a clinical candidate.

MeSH terms

  • Administration, Oral
  • Animals
  • Brain / metabolism*
  • Humans
  • Mice
  • Narcotic Antagonists*
  • Nitriles / administration & dosage
  • Nitriles / chemistry*
  • Nitriles / pharmacokinetics
  • Nociceptin Receptor
  • Pyrazoles / administration & dosage
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacokinetics
  • Rats
  • Receptors, Opioid / metabolism
  • Structure-Activity Relationship

Substances

  • 3-(5-(3,5-difluorophenyl)-3-((((1S,3R)-3-fluorocyclopentyl)amino)methyl)-4-methyl-1H-pyrazol-1-yl)propanenitrile
  • Narcotic Antagonists
  • Nitriles
  • Pyrazoles
  • Receptors, Opioid
  • Nociceptin Receptor