Identification of MK-1925: a selective, orally active and brain-penetrable opioid receptor-like 1 (ORL1) antagonist.
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.
Kobayashi
Kensuke
K
Tsukuba Research Institute, Banyu Pharmaceutical Co, Ltd, Okubo-3, Tsukuba, Ibaraki 300-2611, Japan.
Tsujita
Tomohiro
T
Ito
Hirokatsu
H
Ozaki
Satoshi
S
Tani
Takeshi
T
Ishii
Yasuyuki
Y
Okuda
Shoki
S
Tadano
Kiyoshi
K
Fukuroda
Takahiro
T
Ohta
Hisashi
H
Okamoto
Osamu
O
D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009292:Narcotic Antagonists; D009570:Nitriles / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
C543967:3-(5-(3,5-difluorophenyl)-3-((((1S,3R)-3-fluorocyclopentyl)amino)methyl)-4-methyl-1H-pyrazol-1-yl)propanenitrile; D009292:Narcotic Antagonists; D009570:Nitriles; D011720:Pyrazoles; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor