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Redesigning of the cap conformation and symmetry of the diphenylethyne core to yield highly potent pan-genotypic NS5A inhibitors with high potency and high resistance barrier

Herein, we report the discovery of several NS5A inhibitors with potency against HCV genotype 1b in the picomolar range. Compounds (15, 33) were of extremely high potency against HCV genotype 1b (EC50 ≈ 1 pM), improved activity against genotype 3a (GT 3a) and good metabolic stability. We studied the...

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Main Authors: Abdallah, Mennatallah (Author) , Hamed, Mostafa M. (Author) , Frakolaki, Efseveia (Author) , Katsamakas, Sotirios (Author) , Vassilaki, Niki (Author) , Bartenschlager, Ralf (Author) , Zoidis, Grigoris (Author) , Hirsch, Anna K. H. (Author) , Abdel-Halim, Mohammad (Author) , Abadi, Ashraf H. (Author)
Format: Article (Journal)
Language:English
Published: 5 February 2022
In: European journal of medicinal chemistry
Year: 2022, Volume: 229, Pages: 1-20
ISSN:1768-3254
DOI:10.1016/j.ejmech.2021.114034
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ejmech.2021.114034
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0223523421008837
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Author Notes:Mennatallah Abdallah, Mostafa M. Hamed, Efseveia Frakolaki, Sotirios Katsamakas, Niki Vassilaki, Ralf Bartenschlager, Grigoris Zoidis, Anna K.H. Hirsch, Mohammad Abdel-Halim, Ashraf H. Abadi
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Summary:Herein, we report the discovery of several NS5A inhibitors with potency against HCV genotype 1b in the picomolar range. Compounds (15, 33) were of extremely high potency against HCV genotype 1b (EC50 ≈ 1 pM), improved activity against genotype 3a (GT 3a) and good metabolic stability. We studied the impact of changing the cap conformation relative to the diphenylethyne core and/or compound symmetry on both potency and metabolic stability. The analogs obtained exhibited improved potency against HCV genotypes 1a, 1b, 3a and 4a compared to the clinically approved candidate daclatasvir with EC50 values in the low picomolar range and SI50s > 7 orders of magnitude. Compound 15, a symmetrically m-, m’-substituted diphenyl ethyne analog, was 150-fold more potent than daclatasvir against GT 3a, while compound 33, an asymmetrically m-, p-substituted diphenyl ethyne analog, was 35-fold more potent than daclatasvir against GT 3a. In addition, compound 15 exhibited a higher resistance barrier than daclatasvir against genotype 1b.
Item Description:Online veröffentlicht am 7. Dezember 2021, Artikelversion vom 24. Dezember 2021
Gesehen am 09.01.2023
Physical Description:Online Resource
ISSN:1768-3254
DOI:10.1016/j.ejmech.2021.114034

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