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

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 51 Issue 7 Pg. 2115-27 (Apr 10 2008) ISSN: 0022-2623 [Print] United States
• PMID: 18335976 (Publication Type: Journal Article)

Chemical References

• (2-(2,4-dichlorophenyl)-6-fluoro-2-(4-fluorophenyl)benzo(1,3)dioxol-5-yl)morpholin-4-ylmethanone
• Anti-Obesity Agents
• Benzodioxoles
• Cyclohexanols
• Ligands
• Receptor, Cannabinoid, CB1
• 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol

Topics

• Animals
• Anti-Obesity Agents (administration & dosage, chemistry, pharmacology)
• Benzodioxoles (administration & dosage, chemical synthesis, chemistry, pharmacology)
• Body Weight (drug effects)
• Crystallography, X-Ray
• Cyclohexanols (antagonists & inhibitors, pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Design
• Humans
• Hypothermia (chemically induced)
• Ligands
• Male
• Mice
• Microsomes (drug effects)
• Models, Molecular
• Molecular Structure
• Obesity (drug therapy)
• Rats
• Rats, Sprague-Dawley
• Receptor, Cannabinoid, CB1 (agonists, chemistry)
• Structure-Activity Relationship