ABSTRACT
Novel anthranilamides were surprisingly found to exert additional activity on B-RAF. Corresponding thiophene, pyrazole, and thiazole core analogs were prepared as VEGFR-2 inhibitors with c-KIT, and B-RAF activity. Compounds in the phenyl, thiophene, and thiazole series are in vivo active.
Subject(s)
Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Humans , Mice , Protein Kinase Inhibitors/therapeutic use , Structure-Activity RelationshipABSTRACT
Several imidazole-based cyclohexyl amides were identified as potent CB-1 antagonists, but they exhibited poor oral exposure in rodents. Incorporation of a hydroxyl moiety on the cyclohexyl ring provided a dramatic improvement in oral exposure, together with a ca. 10-fold decrease in potency. Further optimization provided the imidazole 2-hydroxy-cyclohexyl amide 45, which exhibited hCB-1 K(i)=3.7nM, and caused significant appetite suppression and robust, dose-dependent reduction of body weight gain in industry-standard rat models.
Subject(s)
Anti-Obesity Agents/pharmacology , Body Weight/drug effects , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Animals , Anti-Obesity Agents/therapeutic use , Dose-Response Relationship, Drug , Imidazoles/pharmacology , Imidazoles/therapeutic use , Obesity/drug therapy , Rats , Rats, Zucker , Receptors, Cannabinoid/metabolism , Structure-Activity RelationshipABSTRACT
A series of pyrrolopyridinones was designed and synthesized as constrained analogs of the pyrazole CB-1 antagonist rimonabant. Certain examples exhibited very potent hCB-1 receptor binding affinity and functional antagonism with Ki and Kb values below 10 nM, and with high selectivity for CB-1 over CB-2 (>100-fold). A representative analog was established to cause significant appetite suppression and reduction in body weight gain in industry-standard rat models used to develop new therapeutics for obesity.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyridones/chemical synthesis , Pyrroles/chemical synthesis , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Animals , Anti-Obesity Agents/pharmacokinetics , Body Weight/drug effects , Crystallography, X-Ray , Drug Design , Eating/drug effects , Humans , Magnetic Resonance Spectroscopy , Male , Models, Molecular , Obesity/drug therapy , Pyridones/pharmacokinetics , Pyridones/pharmacology , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , Rats, Wistar , Rats, Zucker , Rimonabant , Structure-Activity Relationship , Weight Gain/drug effectsABSTRACT
A series of (5-(2H)-isoxazolonyl) ureas were developed as nanomolar inhibitors of hormone-sensitive lipase, an enzyme of potential importance in the treatment of diabetes.
