title: 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.affiliation: Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Leo
authors.initials: L
authors.lastname: Alig
authors.forename: Jochem
authors.initials: J
authors.lastname: Alsenz
authors.forename: Mirjana
authors.initials: M
authors.lastname: Andjelkovic
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bendels
authors.forename: Agnès
authors.initials: A
authors.lastname: Bénardeau
authors.forename: Konrad
authors.initials: K
authors.lastname: Bleicher
authors.forename: Anne
authors.initials: A
authors.lastname: Bourson
authors.forename: Pascale
authors.initials: P
authors.lastname: David-Pierson
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Guba
authors.forename: Stefan
authors.initials: S
authors.lastname: Hildbrand
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kube
authors.forename: Thomas
authors.initials: T
authors.lastname: Lübbers
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Mayweg
authors.forename: Robert
authors.initials: R
authors.lastname: Narquizian
authors.forename: Werner
authors.initials: W
authors.lastname: Neidhart
authors.forename: Matthias
authors.initials: M
authors.lastname: Nettekoven
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Plancher
authors.forename: Cynthia
authors.initials: C
authors.lastname: Rocha
authors.forename: Mark
authors.initials: M
authors.lastname: Rogers-Evans
authors.forename: Stephan
authors.initials: S
authors.lastname: Röver
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
authors.forename: Sven
authors.initials: S
authors.lastname: Taylor
authors.forename: Pius
authors.initials: P
authors.lastname: Waldmeier
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D052117:Benzodioxoles / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D018360:Crystallography, X-Ray; D003511:Cyclohexanols / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced; D008024:Ligands; D008297:Male; D051379:Mice; D008861:Microsomes / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: C529448:(2-(2,4-dichlorophenyl)-6-fluoro-2-(4-fluorophenyl)benzo(1,3)dioxol-5-yl)morpholin-4-ylmethanone; D019440:Anti-Obesity Agents; D052117:Benzodioxoles; D003511:Cyclohexanols; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol