Benzodioxoles:: Novel cannabinoid-1 receptor inverse Agonists for the treatment of obesity
Benzodioxoles:: Novel cannabinoid-1 receptor inverse Agonists for the treatment of obesity
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DOI：
10.1021/jm701487t
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发表时间：
2008-04-10
影响因子：
7.3
通讯作者：
Waldineier, Pius
中科院分区：
文献类型：
--
作者：
Alig, Leo;Alsenz, Jochern;Waldineier, Pius
基于进化片段的从头设计工具拓扑分配系统(TOPAS)的应用，从一个已知的CBIR(CB-1受体)配体开始，遵循进一步的改进原则，包括药效团顺应性、化学可操作性和药物相似性，使得苯二恶酚能够被鉴定为一种新的CB I R反向激动剂系列。广泛的多维优化得到了有前景的先导化合物的鉴定，显示了体内的活性。这些化合物逆转了CP-55940诱导的海军医学研究所(海军医学研究所)小鼠的低温，并减少了饮食诱导的肥胖SD大鼠的体重增加和脂肪质量。在这里，我们公开了用于快速鉴定、合成和产生结构-活性关系的工具和策略，最终导致鉴定(+)-[(R)-2-(2，4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1，3]dioxol-5-yl]-morpholin-4-yl-metha-None(R)-14g。讨论了(R)-14G的生化、药代动力学和药效学特征。
The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CBIR (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chemical tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB I R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compounds, showing in vivo activity. These compounds reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-weight gain, as well as fat mass, in diet-induced obese Sprague-Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure-activity relationships, ultimately leading to the identification of (+)-[(R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-metha- none (R)-14g. Biochemical, pharmacokinetic, and pharmacodynamic characteristics of (R)-14g are discussed.