ABSTRACT
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.
Subject(s)
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/chemistryABSTRACT
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.
Subject(s)
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 therapyABSTRACT
The SAR development is described for a series of N-acyl pyrrolidine inhibitors of the Hepatitis C virus RNA-dependent RNA polymerase, NS5B, from tractable Delta21 enzyme inhibitors to an example with antiviral activity in a cellular assay (HCV replicon).
Subject(s)
Antiviral Agents/pharmacology , Chemistry, Pharmaceutical/methods , Hepacivirus/chemistry , Hepacivirus/genetics , Pyrrolidines/antagonists & inhibitors , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Replicon/genetics , Viral Nonstructural Proteins/pharmacology , Antiviral Agents/chemistry , Drug Design , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , RNA, Viral/chemistry , Viral Nonstructural Proteins/chemistry , Virus Replication/drug effectsABSTRACT
HTS of the compound collection for inhibition of the HCV RNA dependent RNA polymerase identified two 168 member N-acyl pyrrolidine combinatorial mixture hits. Deconvolution and expansion of these mixtures by solid phase synthesis to establish initial SAR and identify a potent inhibitor is reported.
