Details

Autor(en) / Beteiligte

• Alig, Leo
• Alsenz, Jochem
• Andjelkovic, Mirjana
• Bendels, Stefanie
• Bénardeau, Agnès
• Bleicher, Konrad
• Bourson, Anne
• David-Pierson, Pascale
• Guba, Wolfgang
• Hildbrand, Stefan
• Kube, Dagmar
• Lübbers, Thomas
• Mayweg, Alexander V
• Narquizian, Robert
• Neidhart, Werner
• Nettekoven, Matthias
• Plancher, Jean-Marc
• Rocha, Cynthia
• Rogers-Evans, Mark
• Röver, Stephan
• Schneider, Gisbert
• Taylor, Sven
• Waldmeier, Pius

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2008-04, Vol.51 (7), p.2115-2127

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2008

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.