Abstract
A series of trifluoromethyl ketones as SARS-CoV 3CL protease inhibitors was developed. The inhibitors were synthesized in four steps from commercially available compounds. Three different amino acids were explored in the P1-position and in the P2-P4 positions varying amino acids and long alkyl chain were incorporated. All inhibitors were evaluated in an in vitro assay using purified enzyme and fluorogenic substrate peptide. One of the inhibitors showed a time-dependent inhibition, with a K(i) value of 0.3 microM after 4h incubation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Coronavirus 3C Proteases
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Cysteine Endopeptidases / chemistry
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Cysteine Endopeptidases / metabolism*
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Drug Design
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Fluorine Compounds / chemical synthesis
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Fluorine Compounds / chemistry
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Fluorine Compounds / pharmacology
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Hydrogen Bonding
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Ketones / chemical synthesis*
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Ketones / chemistry
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Ketones / pharmacology*
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Methylation
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Models, Molecular
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Molecular Structure
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology*
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Severe acute respiratory syndrome-related coronavirus / enzymology*
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Viral Proteins / antagonists & inhibitors*
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Viral Proteins / chemistry
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Viral Proteins / metabolism*
Substances
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Fluorine Compounds
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Ketones
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Protease Inhibitors
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Viral Proteins
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Cysteine Endopeptidases
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Coronavirus 3C Proteases