GSK2818713, a Novel Biphenylene Scaffold-Based Hepatitis C NS5A Replication Complex Inhibitor with Broad Genotype Coverage.
J Med Chem
; 63(8): 4155-4170, 2020 04 23.
Article
em En
| MEDLINE
| ID: mdl-32202782
ABSTRACT
Pan-genotype NS5A inhibitors underpin hugely successful hepatitis C virus (HCV) therapy. The discovery of GSK2818713 (13), a nonstructural protein 5A (NS5A) HCV inhibitor characterized by a significantly improved genotype coverage relative to first-generation NS5A inhibitor daclatasvir (DCV), is detailed herein. The SAR analysis revealed cooperative potency effects of the biphenylene, bicyclic pyrrolidine (Aoc), and methyl-threonine structural motifs. Relative to DCV, 13 improved activity against genotype 1a (gt1a) and gt1b NS5A variants as well as HCV chimeric replicons containing NS5A fragments from genotypes 2-6. Long-term treatment of subgenomic replicons with 13 potently and durably decreased HCV RNA levels for gt1a, gt2a, and gt3a. These properties, suitable pharmacokinetics, and the lack of cross-resistance resulted in the selection of 13 as a preclinical candidate.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Antivirais
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Replicação Viral
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Proteínas não Estruturais Virais
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Genótipo
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article