RESUMEN
Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants, the elderly, and immune-compromised patients. While a half-life extended monoclonal antibody and 2 vaccines have recently been approved for infants and the elderly, respectively, options to prevent disease in immune-compromised patients are still needed. Here, we describe spiro-azetidine oxindoles as small molecule RSV entry inhibitors displaying favorable potency, developability attributes, and long-acting PK when injected as an aqueous suspension, suggesting their potential to prevent complications following RSV infection over a period of 3 to 6 months with 1 or 2 long-acting intramuscular (IM) or subcutaneous (SC) injections in these immune-compromised patients.
Asunto(s)
Antivirales , Azetidinas , Oxindoles , Infecciones por Virus Sincitial Respiratorio , Compuestos de Espiro , Humanos , Infecciones por Virus Sincitial Respiratorio/prevención & control , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Animales , Oxindoles/química , Oxindoles/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/administración & dosificación , Antivirales/farmacología , Antivirales/química , Antivirales/administración & dosificación , Azetidinas/química , Azetidinas/farmacología , Azetidinas/administración & dosificación , Azetidinas/farmacocinética , Profilaxis Pre-Exposición/métodos , Inyecciones Intramusculares , Indoles/química , Indoles/administración & dosificación , Indoles/farmacología , Inyecciones Subcutáneas , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Internalización del Virus/efectos de los fármacosRESUMEN
Respiratory syncytial virus (RSV) can cause pulmonary complications in infants, elderly and immunocompromised patients. While two vaccines and two prophylactic monoclonal antibodies are now available, treatment options are still needed. JNJ-7184 is a non-nucleoside inhibitor of the RSV-Large (L) polymerase, displaying potent inhibition of both RSV-A and -B strains. Resistance selection and hydrogen-deuterium exchange experiments suggest JNJ-7184 binds RSV-L in the connector domain. JNJ-7184 prevents RSV replication and transcription by inhibiting initiation or early elongation. JNJ-7184 is effective in air-liquid interface cultures and therapeutically in neonatal lambs, acting to drastically reverse the appearance of lung pathology.