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

• Published in: Journal of medicinal chemistry Vol. 51; no. 7; pp. 2115 - 2127
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.04.2008; Amer Chemical Soc
• Subjects: Animals; Anti-Obesity Agents - administration & dosage; Anti-Obesity Agents - chemistry; Anti-Obesity Agents - pharmacology; Benzodioxoles - administration & dosage; Benzodioxoles - chemical synthesis; Benzodioxoles - chemistry; Benzodioxoles - pharmacology; Biological and medical sciences; Body Weight - drug effects; Chemistry, Medicinal; Crystallography, X-Ray; Cyclohexanols - antagonists & inhibitors; Cyclohexanols - pharmacology; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; General and cellular metabolism. Vitamins; Humans; Hypothermia - chemically induced; Life Sciences & Biomedicine; Ligands; Male; Medical sciences; Mice; Microsomes - drug effects; Miscellaneous; Models, Molecular; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Obesity - drug therapy; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1 - agonists; Receptor, Cannabinoid, CB1 - chemistry; Science & Technology; Structure-Activity Relationship; DE-NOVO DESIGN; RISK-FACTORS; LIGANDS; MK-0364; CB1 cannabinoid receptor; Obesity; Rat; Rodentia; Nutrition disorder; Clearance; Morpholine derivatives; Vertebrata; Mammalia; Treatment; Structure activity relation; Mouse; Inverse agonist; Animal; Chlorine Organic compounds; Fluorine Organic compounds; R configuration; Pharmacokinetics; Chemical synthesis; Nutritional status
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm701487t

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.