Benzodioxoles: Novel Cannabinoid-1 Receptor Inverse Agonists for the Treatment of Obesity

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• 作者：Leo Alig ; Jochem Alsenz ; Mirjana Andjelkovic ; Stefanie Bendels ; Agnè ; s Bé ; nardeau ; Konrad Bleicher ; Anne Bourson ; Pascale David-Pierson ; Wolfgang Guba ; Stefan Hildbrand ; Dagmar Kube ; Thomas L&
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：April 10, 2008
• 年：2008
• 卷：51
• 期：7
• 页码：2115 - 2127
• 全文大小：1600K
• 年卷期：v.51,no.7(April 10, 2008)
• ISSN：1520-4804

文摘

The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (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 CB1R 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-methanone (R)-14g. Biochemical, pharmacokinetic, and pharmacodynamic characteristics of (R)-14g are discussed.