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J Med Chem. 2008 Jul 10;51(13):4021-9. doi: 10.1021/jm701590h. Epub 2008 Jun 7.

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.

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Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan.


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.

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