RESUMEN
Several different heterocyclic systems were compared as PDE5 inhibitor scaffolds. In addition to the known 3H-imidazo[5,1-f][1,2,4]triazin-4-ones and pyrazolopyrimidinones, isomeric imidazo[1,5-a][1,3,5]triazin-4(3H)-ones were also shown to be potent and selective PDE inhibitor scaffolds with in vivo activity. SAR trends were elucidated for sulfonamide derivatives with generality across different scaffolds.
Asunto(s)
3',5'-GMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Compuestos Heterocíclicos/síntesis química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Compuestos Heterocíclicos/farmacología , Concentración 50 Inhibidora , Relación Estructura-Actividad , Especificidad por SustratoAsunto(s)
Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/química , 3',5'-GMP Cíclico Fosfodiesterasas , GMP Cíclico/fisiología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Disfunción Eréctil/tratamiento farmacológico , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Masculino , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/uso terapéutico , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/fisiología , Pirimidinonas/farmacología , Relación Estructura-ActividadRESUMEN
Chronic hepatitis B virus (HBV) infection is a major cause of liver disease. Only interferon-alpha and the nucleosidic inhibitors of the viral polymerase, 3TC and adefovir, are approved for therapy. However, these therapies are limited by the side effects of interferon and the substantial resistance of the virus to nucleosidic inhibitors. Potent new antiviral compounds suitable for monotherapy or combination therapy are highly desired. We describe non-nucleosidic inhibitors of HBV nucleocapsid maturation that possess in vitro and in vivo antiviral activity. These inhibitors have potential for future therapeutic regimens to combat chronic HBV infection.
Asunto(s)
Acetilcisteína/análogos & derivados , Antivirales/farmacología , Virus de la Hepatitis B/efectos de los fármacos , Nucleocápside/metabolismo , Piridinas/farmacología , Pirimidinas/farmacología , Triazoles/farmacología , Acetilcisteína/farmacología , Sustitución de Aminoácidos , Antivirales/química , Antivirales/metabolismo , Sitios de Unión , Cápside/metabolismo , Replicación del ADN/efectos de los fármacos , ADN Viral/biosíntesis , Semivida , Virus de la Hepatitis B del Pato/efectos de los fármacos , Virus de la Hepatitis B del Pato/metabolismo , Virus de la Hepatitis B/fisiología , Humanos , Mutación , Piridinas/química , Piridinas/metabolismo , Pirimidinas/química , Pirimidinas/metabolismo , Proteínas Recombinantes/metabolismo , Estereoisomerismo , Triazoles/química , Triazoles/metabolismo , Células Tumorales Cultivadas , Proteínas del Núcleo Viral/química , Proteínas del Núcleo Viral/genética , Proteínas del Núcleo Viral/metabolismo , Ensamble de Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
2-aryl-substituted imidazo[5,1-f][1,2,4]triazin-4(3H)-ones represent a new class of potent cGMP-PDE 5 inhibitors that prove to be superior to other purine-isosteric inhibitors. Subnanomolar inhibitors of PDE 5 with activity in in vivo models for erectile dysfunction have been identified. BAY 38-9456 (Vardenafil-hydrochloride) has been selected for clinical studies in the indication of erectile dysfunction.