Benzodioxoles: novel cannabinoid-1 receptor inverse agonists for the treatment of obesity.
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.
Alig
Leo
L
Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Alsenz
Jochem
J
Andjelkovic
Mirjana
M
Bendels
Stefanie
S
Bénardeau
Agnès
A
Bleicher
Konrad
K
Bourson
Anne
A
David-Pierson
Pascale
P
Guba
Wolfgang
W
Hildbrand
Stefan
S
Kube
Dagmar
D
Lübbers
Thomas
T
Mayweg
Alexander V
AV
Narquizian
Robert
R
Neidhart
Werner
W
Nettekoven
Matthias
M
Plancher
Jean-Marc
JM
Rocha
Cynthia
C
Rogers-Evans
Mark
M
Röver
Stephan
S
Schneider
Gisbert
G
Taylor
Sven
S
Waldmeier
Pius
P
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
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