A Novel Class of Cycloalkano[b]pyridines as Potent and Orally Active Opioid Receptor-like 1 Antagonists with Minimal Binding Affinity to the hERG K+ Channel

A series of compounds based on 7-{[4-(2-methylphenyl)piperidin-1-yl]methyl}-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-9-ol ((−)-8b), a potent and selective opioid receptor-like 1 (ORL1) antagonist, was prepared and evaluated using structure−activity relationship studies with the aim of removing it...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2008-07, Vol.51 (13), p.4021-4029
Main Authors: Yoshizumi, Takashi, Takahashi, Hirobumi, Miyazoe, Hiroshi, Sugimoto, Yuichi, Tsujita, Tomohiro, Kato, Tetsuya, Ito, Hirokatsu, Kawamoto, Hiroshi, Hirayama, Mioko, Ichikawa, Daisuke, Azuma-Kanoh, Tomoko, Ozaki, Satoshi, Shibata, Yoshihiro, Tani, Takeshi, Chiba, Masato, Ishii, Yasuyuki, Okuda, Shoki, Tadano, Kiyoshi, Fukuroda, Takahiro, Okamoto, Osamu, Ohta, Hisashi
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Biological and medical sciences
Chemical Phenomena
Chemistry, Physical
Cycloparaffins - chemistry
Dogs
Ether-A-Go-Go Potassium Channels - antagonists & inhibitors
Ether-A-Go-Go Potassium Channels - metabolism
Hepatocytes - metabolism
Humans
Medical sciences
Molecular Structure
Narcotic Antagonists
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Protein Binding
Pyridines - administration & dosage
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - classification
Rats
Receptors, Opioid - metabolism
Structure-Activity Relationship
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Summary:A series of compounds based on 7-{[4-(2-methylphenyl)piperidin-1-yl]methyl}-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-9-ol ((−)-8b), a potent and selective opioid receptor-like 1 (ORL1) antagonist, was prepared and evaluated using structure−activity relationship studies with the aim of removing its affinity to human ether-a-go-go related gene (hERG) K+ channel. From these studies, 10l was identified as an optimized structure with respect to ORL1 antagonist activity, and affinity to the hERG K+channel. Furthermore, 10l showed good in vivo antagonism with a wide therapeutic index in regards to adverse cardiovascular effects.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm701590h