RESUMEN
High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/química , Pirimidinonas/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Tiofenos/química , Administración Oral , Animales , Dolor Crónico/tratamiento farmacológico , Modelos Animales de Enfermedad , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Pirimidinonas/síntesis química , Pirimidinonas/uso terapéutico , Ratas , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/uso terapéuticoRESUMEN
A series of fused tricyclic mGluR1 antagonists containing a pyridone ring were synthesized. In vitro, these antagonists were potent against both human and rat isozymes, as well as selective for inhibiting mGluR1 over mGluR5. When dosed orally, several examples were active in vivo in a rat SNL test.
Asunto(s)
Piridonas/síntesis química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Administración Oral , Analgésicos/farmacología , Animales , Células Cultivadas , Ciclización , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Neuralgia/tratamiento farmacológico , Unión Proteica/efectos de los fármacos , Piridonas/química , Piridonas/farmacología , RatasRESUMEN
Securamine A is a structurally intriguing alkaloid possessing a pyrroloindole core joined via a modified isoprene subunit to a functionalized imidazole ring. Recent synthetic efforts in this laboratory have resulted in the efficient construction of key lactone 36, which undergoes tandem azide reduction/ring expansion to macrolactam 37. Macrolactam 37 possesses the complete macrocyclic core of securamine A.
