2. Academic Validation
  3. Benzodioxoles: novel cannabinoid-1 receptor inverse agonists for the treatment of obesity

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

  • J Med Chem. 2008 Apr 10;51(7):2115-27. doi: 10.1021/jm701487t.
Leo Alig 1,  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
Affiliations

Affiliation

  • 1 Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
PMID: 18335976 DOI: 10.1021/jm701487t
Abstract

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.

Figures
Products