RESUMO
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.
Assuntos
Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/farmacologia , Benzodioxóis/administração & dosagem , Benzodioxóis/farmacologia , Obesidade/tratamento farmacológico , Receptor CB1 de Canabinoide/agonistas , Animais , Fármacos Antiobesidade/química , Benzodioxóis/síntese química , Benzodioxóis/química , Peso Corporal/efeitos dos fármacos , Cristalografia por Raios X , Cicloexanóis/antagonistas & inibidores , Cicloexanóis/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Hipotermia/induzido quimicamente , Ligantes , Masculino , Camundongos , Microssomos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/química , Relação Estrutura-AtividadeRESUMO
We describe the structure-based design and synthesis of highly potent, orally bioavailable tissue factor/factor VIIa inhibitors which interfere with the coagulation cascade by selective inhibition of the extrinsic pathway.