Discovery and Optimization of 1-(4-(Pyridin-2-yl)benzyl)imidazolidine-2,4-dione Derivatives As a Novel Class of Selective Cannabinoid CB2 Receptor Agonists

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• 作者：Mario van der Stelt ; Jos Cals ; Silvia Broeders-Josten ; Jean Cottney ; Antoon A. van der Doelen ; Marcel Hermkens ; Vera de Kimpe ; Angela King ; Jan Klomp ; Julia Oosterom ; Ilse Pols-de Rooij ; Jeroen de Roos ; Martin van Tilborg ; Susan Boyce ; James Baker
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 27, 2011
• 年：2011
• 卷：54
• 期：20
• 页码：7350-7362
• 全文大小：1194K
• 年卷期：v.54,no.20(October 27, 2011)
• ISSN：1520-4804

文摘

Here, we report the identification and optimization of 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives as a novel chemotype with selective cannabinoid CB2 receptor agonist activity. 1 is a potent and selective cannabinoid CB2 receptor agonist (hCB2 pEC₅₀ = 8.6). The compound was found to be metabolically unstable, which resulted in low oral bioavailability in rat (F_po = 4%) and possessed off-target activity at the hERG ion channel (pK_i = 5.5). Systematic modification of physicochemical properties, such as lipophilicity and basicity, was used to optimize the pharmacokinetic profile and hERG affinity of this novel class of cannabinoid CB2 receptor agonists. This led to the identification of 44 as a potent, selective, and orally bioavailable cannabinoid CB2 receptor agonist (hCB2 pEC₅₀ = 8.0; hERG pK_i < 4; F_po = 100%), which was active in a rat spinal nerve ligation model of neuropathic pain.