Pan-NS3 protease inhibitors of hepatitis C virus based on an R 3 -elongated pyrazinone scaffold

Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors and show that elongated R urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on β-sheet mimicking hydrogen bonds...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2018-03, Vol.148, p.453
Main Authors: Belfrage, Anna Karin, Abdurakhmanov, Eldar, Åkerblom, Eva, Brandt, Peter, Alogheli, Hiba, Neyts, Johan, Danielson, U Helena, Sandström, Anja
Format: Article
Language:English
Subjects:
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Genotype
Hepacivirus - enzymology
Humans
Hydrogen Bonding
Protein Conformation, beta-Strand
Pyrazines - chemistry
Viral Nonstructural Proteins - antagonists & inhibitors
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Summary:Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors and show that elongated R urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on β-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the β-sheet interactions of the natural peptide substrate. Inhibitor 36, for example, with a urea substituent including a cyclic imide showed balanced nanomolar inhibitory potencies against genotype 1a, both wild-type (K  = 30 nM) and R155K (K  = 2 nM), and genotype 3a (K  = 5 nM).
ISSN:1768-3254