2. Academic Validation
  3. Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold

Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold

  • Eur J Med Chem. 2018 Mar 25:148:453-464. doi: 10.1016/j.ejmech.2018.02.032.
Anna Karin Belfrage 1,  Eldar Abdurakhmanov 2,  Eva Åkerblom 3,  Peter Brandt 3,  Hiba Alogheli 3,  Johan Neyts 4,  U Helena Danielson 2,  Anja Sandström 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Uppsala University, Box 574, SE-75123 Uppsala, Sweden. Electronic address: annakarin.belfrage@ilk.uu.se.
  • 2 Department of Chemistry-BMC, Uppsala University, Box 576, SE-75123 Uppsala, Sweden.
  • 3 Department of Medicinal Chemistry, Uppsala University, Box 574, SE-75123 Uppsala, Sweden.
  • 4 Rega Institute, Department of Microbiology and Immunology, University of Leuven, B-3000 Leuven, Belgium.
PMID: 29477077 DOI: 10.1016/j.ejmech.2018.02.032
Abstract

Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 Protease Inhibitors and show that elongated R3 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 (Ki = 30 nM) and R155K (Ki = 2 nM), and genotype 3a (Ki = 5 nM).

Keywords

Genotype 3; Hepatitis C; NS3; Pyrazinone; Resistance.

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