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
| Autor: | Takeshi Tani, Hisashi Ohta, Tetsuya Kato, Tomohiro Tsujita, Hirobumi Takahashi, Hirokatsu Ito, Mioko Hirayama, Kiyoshi Tadano, Tomoko Azuma-Kanoh, Hiroshi Kawamoto, Masato Chiba, Daisuke Ichikawa, Osamu Okamoto, Yuichi Sugimoto, Takahiro Fukuroda, Yoshihiro Shibata, Satoshi Ozaki, Takashi Yoshizumi, Shoki Okuda, Hiroshi Miyazoe, Yasuyuki Ishii |
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| Rok vydání: | 2008 |
| Předmět: |
Chemical Phenomena
Pyridines Stereochemistry Narcotic Antagonists hERG Administration Oral Pharmacology Nociceptin Receptor Structure-Activity Relationship Dogs Therapeutic index In vivo Drug Discovery medicine Animals Humans Molecular Structure Bicyclic molecule biology Chemistry Physical Chemistry Antagonist Cycloparaffins Ether-A-Go-Go Potassium Channels Rats Nociceptin receptor Opioid Receptors Opioid Hepatocytes biology.protein Molecular Medicine Antagonism Protein Binding medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 51:4021-4029 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm701590h |
| Popis: | A series of compounds based on 7-{[4-(2-methylphenyl)piperidin-1-yl]methyl}-6,7,8,9-tetrahydro-5 H-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. |
| Databáze: | OpenAIRE |
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