RESUMO
Respiratory syncytial virus (RSV) is an RNA virus infecting the upper and lower respiratory tract and is recognized as a major respiratory health threat, particularly to older adults, immunocompromised individuals, and young children. Around 64 million children and adults are infected every year worldwide. Despite two vaccines and a new generation monoclonal antibody recently approved, no effective antiviral treatment is available. In this manuscript, we present the medicinal chemistry efforts resulting in the identification of compound 28 (JNJ-8003), a novel RSV non-nucleoside inhibitor displaying subnanomolar activity in vitro as well as prominent efficacy in mice and a neonatal lamb models.
Assuntos
Antivirais , Piridinas , Animais , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Humanos , Camundongos , Piridinas/farmacologia , Piridinas/química , Piridinas/síntese química , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Relação Estrutura-Atividade , Ovinos , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Vírus Sinciciais Respiratórios/efeitos dos fármacosRESUMO
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.
Assuntos
Antivirais , Azetidinas , Oxindóis , Infecções por Vírus Respiratório Sincicial , Compostos de Espiro , Humanos , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Animais , Oxindóis/química , Oxindóis/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Compostos de Espiro/farmacocinética , Compostos de Espiro/administração & dosagem , Antivirais/farmacologia , Antivirais/química , Antivirais/administração & dosagem , Azetidinas/química , Azetidinas/farmacologia , Azetidinas/administração & dosagem , Azetidinas/farmacocinética , Profilaxia Pré-Exposição/métodos , Injeções Intramusculares , Indóis/química , Indóis/administração & dosagem , Indóis/farmacologia , Injeções Subcutâneas , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacosRESUMO
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.