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.
Antiviral Agents , Coronavirus Protease Inhibitors , Furans , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Lactams , Peptide Hydrolases , Protease Inhibitors/pharmacology , Protease Inhibitors/chemistry , SARS-CoV-2 , Furans/chemistry , Coronavirus Protease Inhibitors/chemistry
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.
Aminoquinolines/chemical synthesis , Aminoquinolines/pharmacology , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/pharmacology , Purinergic P2 Receptor Antagonists , Aminoquinolines/chemistry , Combinatorial Chemistry Techniques , Humans , Molecular Structure , Platelet Aggregation Inhibitors/chemistry , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2Y1 , Stereoisomerism , Structure-Activity Relationship , Thrombosis/drug therapy
