Benzodioxoles: novel cannabinoid-1 receptor inverse agonists for the treatment of obesity.

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.

Citation

Leo Alig, Jochem Alsenz, Mirjana Andjelkovic, Stefanie Bendels, Agnès Bénardeau, Konrad Bleicher, Anne Bourson, Pascale David-Pierson, Wolfgang Guba, Stefan Hildbrand, Dagmar Kube, Thomas Lübbers, Alexander V Mayweg, Robert Narquizian, Werner Neidhart, Matthias Nettekoven, Jean-Marc Plancher, Cynthia Rocha, Mark Rogers-Evans, Stephan Röver, Gisbert Schneider, Sven Taylor, Pius Waldmeier. Benzodioxoles: novel cannabinoid-1 receptor inverse agonists for the treatment of obesity. Journal of medicinal chemistry. 2008 Apr 10;51(7):2115-27

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PMID: 18335976

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