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

Atsushi Satoh; Takeshi Sagara; Hiroki Sakoh; Masaya Hashimoto; Hiroshi Nakashima; Tetsuya Kato; Yasuhiro Goto; Sayaka Mizutani; Tomoko Azuma-Kanoh; Takeshi Tani; Shoki Okuda; Osamu Okamoto; Satoshi Ozaki; Yoshikazu Iwasawa; Hisashi Ohta; Hiroshi Kawamoto

doi:10.1021/jm900581g

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

J Med Chem. 2009 Jul 23;52(14):4091-4. doi: 10.1021/jm900581g.

Authors

Atsushi Satoh¹, Takeshi Sagara, Hiroki Sakoh, Masaya Hashimoto, Hiroshi Nakashima, Tetsuya Kato, Yasuhiro Goto, Sayaka Mizutani, Tomoko Azuma-Kanoh, Takeshi Tani, Shoki Okuda, Osamu Okamoto, Satoshi Ozaki, Yoshikazu Iwasawa, Hisashi Ohta, Hiroshi Kawamoto

Affiliation

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

PMID: 19537798
DOI: 10.1021/jm900581g

Abstract

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.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Administration, Oral
Animals
Benzimidazoles / administration & dosage*
Benzimidazoles / metabolism
Benzimidazoles / pharmacokinetics
Benzimidazoles / pharmacology*
CHO Cells
Cricetinae
Cricetulus
Humans
Hydrophobic and Hydrophilic Interactions
Inhibitory Concentration 50
Mice
Narcotic Antagonists*
Nociceptin Receptor
Piperidines / administration & dosage*
Piperidines / metabolism
Piperidines / pharmacokinetics
Piperidines / pharmacology*
Rats
Receptors, Opioid / metabolism
Structure-Activity Relationship

Substances

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
ATP Binding Cassette Transporter, Subfamily B, Member 1
Benzimidazoles
Narcotic Antagonists
Piperidines
Receptors, Opioid
Nociceptin Receptor