Novel ORL1-selective antagonists with oral bioavailability and brain penetrability

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• 作者：Osamu Okamoto ; Kensuke Kobayashi ; Hiroshi Kawamoto ; Satoru Ito ; Takashi Yoshizumi ; Izumi Yamamoto ; Masaya Hashimoto ; Atsushi Shimizu ; Hiroyuki Takahashi ; Yasuyuki Ishii ; Satoshi Ozaki ; Hisashi Ohta
• 关键词：Nociceptin/orphanin FQ ; Nociceptin receptor ; Opioid receptor-like 1(ORL1) antagonist
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2008
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 June 2008
• 卷：18
• 期：11
• 页码：3282-3285
• 文件大小：139 K

摘要

Following the discovery of 5-chloro-6-[piperazin-1-yl]-1H-benzimidazole as a novel pharmacophore for potent and selective ORL1 antagonist activity, optimization of this new lead by introduction of a methyl substitution on the piperazine ring resulted in a highly potent and selective, orally available, and brain penetrable ORL1 antagonist, 2-(tert-butylthio)-5-chloro-6-[(2R)-4-(2-hydroxyethyl)-2-methylpiperazin-1-yl]-1H-benzimidazole. Stereochemistry of the methyl substituent on the piperazine ring to control the functional activity of other opioid receptors is also described.