Discovery of Agonists of Cannabinoid Receptor 1 with Restricted Central Nervous System Penetration Aimed for Treatment of Gastroesophageal Reflux Disease

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• 作者：Alleyn T. Plowright ; Karolina Nilsson ; Madeleine Antonsson ; Kosrat Amin ; Johan Broddefalk ; J枚rgen Jensen ; Anders Lehmann ; Shujuan Jin ; Stephane St-Onge ; Miros艂aw J. Tomaszewski ; Maxime Tremblay ; Christopher Walpole ; Zhongyong Wei ; Hua Yang ; Johan Ulander
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：January 10, 2013
• 年：2013
• 卷：56
• 期：1
• 页码：220-240
• 全文大小：640K
• 年卷期：v.56,no.1(January 10, 2013)
• ISSN：1520-4804

文摘

Agonists of the cannabinoid receptor 1 (CB1) have been suggested as possible treatments for a range of medical disorders including gastroesophageal reflux disease (GERD). While centrally acting cannabinoid agonists are known to produce psychotropic effects, it has been suggested that the CB1 receptors in the periphery could play a significant role in reducing reflux. A moderately potent and highly lipophilic series of 2-aminobenzamides was identified through focused screening of GPCR libraries. Development of this series focused on improving potency and efficacy at the CB1 receptor, reducing lipophilicity and limiting the central nervous system (CNS) exposure while maintaining good oral absorption. Improvement of the series led to compounds having excellent potency at the CB1 receptor and high levels of agonism, good physical and pharmacokinetic properties, and low penetration into the CNS. A range of compounds demonstrated a dose-dependent inhibition of transient lower esophageal sphincter relaxations in a dog model.