β-D-2′-deoxy-2′-α-fluoro-2′-β-C-substituted-2-modified-N6-substituted purine nucleotides for HCV treatment
Inventors
Sommadossi, Jean-Pierre • Moussa, Adel
Assignees
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Publication Number
US-10815266-B2
Publication Date
2020-10-27
Expiration Date
Abstract
A compound of the structure: or a pharmaceutically acceptable salt or composition thereof for the treatment of a host infected with or exposed to an HCV virus or other disorders more fully described herein.
Core Innovation
The patent discloses beta-D-2'-deoxy-2'-alpha-fluoro-2'-beta-C-substituted, N6-substituted purine nucleotides and stabilized phosphate prodrugs, including compounds represented by Formulas I through VII and thiophosphoramidates. These chemical entities feature a fluorinated nucleoside scaffold bearing purine base modifications alongside phosphoramidate prodrug moieties. The prodrugs metabolize in vivo into active guanine triphosphate inhibitors that target hepatitis C virus NS5B polymerase.
The independent claim covers a compound of a depicted formula or a pharmaceutically acceptable salt thereof, although the chemical structure is not reproduced in the text. Disclosed compounds, including Compounds 25, 27, and 5-2, inhibit hepatitis C virus replication in a concentration-dependent manner. Because the background section is omitted, the technical problem being solved is not explicitly described in patent.
Claims Coverage
The provided claims identify one independent claim covering one inventive feature.
Compound of a depicted formula or salt thereof
The independent claim covers a compound of the depicted formula, or a pharmaceutically acceptable salt thereof, where the chemical structure is not reproduced in the provided claim text.
The independent claim covers the compound defined by the depicted formula and its pharmaceutically acceptable salts.
Stated Advantages
Compounds 5-2, 25, and 27 show greater antiviral potency than sofosbuvir in HCV replicon and patient-derived genotype assays, with reported replicon EC50 values of 4 nM and therapeutic indices exceeding 25,000.
The tested compounds show no evident cross-resistance to the tested NS5B resistance variants.
Compounds 25, 27, and 5-2 show low cytotoxicity in bone marrow progenitor and cardiomyocyte assays and do not inhibit the tested human DNA polymerases.
Compound 5-2 shows less hepatocyte toxicity than sofosbuvir and INX-189 in human hepatocyte co-cultures.
Documented Applications
Use of the disclosed compounds and prodrugs as anti-HCV agents for treatment or prophylaxis, including administration in combination therapy.
Evaluation of antiviral activity against HCV using HCV replicons and patient-derived genotype assays.
Inhibition of HCV genotype 1b NS5B polymerase and HCV replication.
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