RESUMEN
Influenza viruses (IFVs) have caused several pandemics and have claimed numerous lives since their first record in the early 20th century. While the outbreak of COVID-19 seemed to expel influenza from the sight of people for a short period of time, it is not surprising that it will recirculate around the globe after the coronavirus has mutated into a less fatal variant. Baloxavir marboxil (1), the prodrug of baloxavir (2) and a cap-dependent endonuclease (CEN) inhibitor, were approved by the FDA for the first treatment in almost 20 years. Despite their high antiviral potency, drug-resistant variants have been observed in clinical trials. Herein, we report a novel CEN inhibitor 8 with a delicately designed macrocyclic scaffold that exhibits a significantly smaller shift of inhibitory activity toward baloxavir-resistant variants.
Asunto(s)
Dibenzotiepinas , Gripe Humana , Morfolinas , Tiepinas , Humanos , Gripe Humana/tratamiento farmacológico , Oxazinas/farmacología , Piridinas/farmacología , Endonucleasas , Antivirales/farmacología , Antivirales/uso terapéutico , Tiepinas/farmacología , Tiepinas/uso terapéutico , Piridonas/farmacología , Piridonas/uso terapéutico , Triazinas/farmacología , Triazinas/uso terapéuticoRESUMEN
[This corrects the article DOI: 10.1021/acsmedchemlett.7b00418.].
RESUMEN
A new series of 3,3'-spirocyclic-2-oxo-indoline derivatives was synthesized and evaluated against respiratory syncytial virus (RSV) in a cell-based assay and animal model. Extensive structure-activity relationship study led to a lead compound 14h, which exhibited excellent in vitro potency with an EC50 value of 0.8 nM and demonstrated 71% oral bioavailability in mice. In a mouse challenge model of RVS infection, 14h demonstrated superior efficacy with a 3.9log RSV virus load reduction in the lung following an oral dose of 50 mg/kg.
