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