Identification of an orally active opioid receptor-like 1 (ORL1) receptor antagonist 4-{3-[(2R)-2,3-dihydroxypropyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-[(1S,3S,4R)-spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropan]-3-ylmethyl]piperidine as clinical candidate.
Our efforts to optimize prototype opioid receptor-like 1 (ORL1) antagonist 1 led to the discovery of 4-{3-[(2R)-2,3-dihydroxypropyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-[(1S,3S,4R)-spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropan]-3-ylmethyl]piperidine 10. 10 showed potent ORL1 antagonistic activity, excellent selectivity over other opioid receptors, and in vivo efficacy after oral dosing. Currently clinical trials of 10 are underway.
Satoh
Atsushi
A
Tsukuba Research Institute, Banyu Pharmaceutical Co, Ltd, Tsukuba 300-2611, Ibaraki, Japan.
Sagara
Takeshi
T
Sakoh
Hiroki
H
Hashimoto
Masaya
M
Nakashima
Hiroshi
H
Kato
Tetsuya
T
Goto
Yasuhiro
Y
Mizutani
Sayaka
S
Azuma-Kanoh
Tomoko
T
Tani
Takeshi
T
Okuda
Shoki
S
Okamoto
Osamu
O
Ozaki
Satoshi
S
Iwasawa
Yoshikazu
Y
Ohta
Hisashi
H
Kawamoto
Hiroshi
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D051379:Mice; D009292:Narcotic Antagonists; D010880:Piperidines / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
C543041:4-(3-(2,3-dihydroxypropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-(spiro(bicyclo(2.2.1)heptane-2,1'-cyclopropan)-3-ylmethyl)piperidine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001562:Benzimidazoles; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor