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

Kensuke Kobayashi; Tomohiro Tsujita; Hirokatsu Ito; Satoshi Ozaki; Takeshi Tani; Yasuyuki Ishii; Shoki Okuda; Kiyoshi Tadano; Takahiro Fukuroda; Hisashi Ohta; Osamu Okamoto

doi:10.1016/j.bmcl.2009.06.051

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.

Authors

Kensuke Kobayashi¹, Tomohiro Tsujita, Hirokatsu Ito, Satoshi Ozaki, Takeshi Tani, Yasuyuki Ishii, Shoki Okuda, Kiyoshi Tadano, Takahiro Fukuroda, Hisashi Ohta, Osamu Okamoto

Affiliation

¹ Tsukuba Research Institute, Banyu Pharmaceutical Co, Ltd, Okubo-3, Tsukuba, Ibaraki 300-2611, Japan.

PMID: 19564110
DOI: 10.1016/j.bmcl.2009.06.051

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