RESUMEN
The virally encoded 3C-like protease (3CLpro) is a well-validated drug target for the inhibition of coronaviruses including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Most inhibitors of 3CLpro are peptidomimetic, with a γ-lactam in place of Gln at the P1 position of the pseudopeptide chain. An effort was pursued to identify a viable alternative to the γ-lactam P1 mimetic which would improve physicochemical properties while retaining affinity for the target. Discovery of a 2-tetrahydrofuran as a suitable P1 replacement that is a potent enzymatic inhibitor of 3CLpro in SARS-CoV-2 virus is described herein.
Asunto(s)
Antivirales , Inhibidores de Proteasa de Coronavirus , Furanos , Antivirales/química , Antivirales/farmacología , Lactamas , Péptido Hidrolasas , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/química , SARS-CoV-2 , Furanos/química , Inhibidores de Proteasa de Coronavirus/químicaRESUMEN
High-throughput screening of the GSK compound collection against the P2Y(1) receptor identified a novel series of tetrahydro-4-quinolinamine antagonists. Optimal substitution around the piperidine group was pivotal for ensuring activity. An exemplar analog from this series was shown to inhibit platelet aggregation.