RESUMEN
Synthesis and structure-activity relationships of cannabinoid-1 receptor (CB1R) inverse agonists based on dihydro-pyrano[2,3-b] pyridine and tetrahydro-1,8-naphtyridine scaffolds are presented. Rat food intake and pharmacokinetic evaluation of 13g, 13i, 13k and 17a revealed these compounds to be highly efficacious orally active modulators of CB1R.
Asunto(s)
Naftiridinas/química , Piridinas/química , Receptor Cannabinoide CB1/agonistas , Pérdida de Peso/efectos de los fármacos , Administración Oral , Animales , Ingestión de Alimentos , Humanos , Naftiridinas/síntesis química , Naftiridinas/farmacología , Farmacocinética , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Receptor Cannabinoide CB1/efectos de los fármacos , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The synthesis, SAR and binding affinities of cannabinoid-1 receptor (CB1R) inverse agonists based on furo[2,3-b]pyridine scaffolds are described. Food intake, mechanism specific efficacy, pharmacokinetic, and metabolic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.
Asunto(s)
Diseño de Fármacos , Furanos/síntesis química , Piridinas/síntesis química , Receptor Cannabinoide CB1/agonistas , Animales , Benzopiranos , Perros , Furanos/química , Furanos/farmacología , Haplorrinos , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Noqueados , Estructura Molecular , Piridinas/química , Piridinas/farmacología , Ratas , Receptor Cannabinoide CB1/genética , Relación Estructura-ActividadRESUMEN
Optimization of the biological activity for 5,6-diarylpyridines as CB1 receptor inverse agonists is described. Food intake and pharmacokinetic evaluation of 3f and 15c indicate that these compounds are effective orally active modulators of CB1.
Asunto(s)
Química Farmacéutica/métodos , Piridinas/química , Piridinas/síntesis química , Receptor Cannabinoide CB1/agonistas , Animales , Conducta Animal/efectos de los fármacos , Diseño de Fármacos , Conducta Alimentaria/efectos de los fármacos , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Temperatura , Tolueno/químicaRESUMEN
Synthesis, SAR, and binding affinities are described for a new class of 1,8-naphthyridinone CB1 receptor specific inverse agonists. Food intake, knockout mouse, and pharmacokinetic evaluation of 14 indicate that this compound is an effective orally active modulator of CB1.