Beta-D-2′-deoxy-2′-alpha-fluoro-2′-beta-C-substituted-2-modified-N6-substituted purine nucleotides for HCV treatment
Inventors
Sommadossi, Jean-Pierre • Moussa, Adel
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10239911-B2
Publication Date
2019-03-26
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 disclosed subject matter concerns ̂-D-2′-deoxy-2′-́-fluoro-2′-̂-C-substituted, N6-substituted purine nucleosides, nucleotides, and stabilized prodrug forms, including 5′-phosphate, phosphoramidate, and thiophosphoramidate analogs. These compounds treat hepatitis C in a host by administering an anti-HCV effective amount of a compound of the specified formulas, or a pharmaceutically acceptable salt thereof. The compounds metabolize to guanine monophosphate and subsequently to an active triphosphate form that inhibits HCV NS5B RNA-dependent RNA polymerase.
Biological evaluations demonstrate activity across clinical HCV genotypes, with representative compounds exhibiting nanomolar potency and lower EC50 values than sofosbuvir in replicon assays. The compounds retain activity without evident cross-resistance against tested NS5B variants, while demonstrating no in-vitro cytotoxicity in bone marrow progenitor cells or cardiomyocytes. Disclosed embodiments encompass treatment or prophylaxis, combination therapies with other antivirals, and formulations such as oral tablets or capsules.
Claims Coverage
The claims recite two inventive features across two independent claims directed to methods for treating hepatitis C.
Treatment of hepatitis C with a first depicted compound
Claim 1 recites a method for treating hepatitis C in a host in need thereof comprising administering an anti-HCV effective amount of a compound of the formula depicted in the claim, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
Treatment of hepatitis C with a second depicted compound
Claim 13 recites a method for treating hepatitis C in a host in need thereof comprising administering an anti-HCV effective amount of a compound of the formula depicted in the claim, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
Both independent claims cover methods of treating hepatitis C by administering an anti-HCV effective amount of the respective claimed compound or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with dependent claims specifying oral administration, tablet or capsule dosage forms, and a human host.
Stated Advantages
Compounds 5-2 and 25 show EC50 values of 4 nM in Huh-7 replicon assays, compared with 53 nM for sofosbuvir, demonstrating nanomolar activity across multiple HCV genotypes and generally greater potency than sofosbuvir.
Representative phosphoramidates show EC50 values of 4–26 nM and therapeutic indices above 25,000 in replicon assays, and the active triphosphate exhibits an HCV NS5B IC50 of 0.15 ́M.
The tested compounds show no evidence of cross-resistance to tested NS5B resistance-associated variants in patient-derived replicons and retain activity against S282T in transient assays.
Compounds 25, 27, and 5-2 show no in-vitro cytotoxicity in bone marrow progenitor cells or cardiomyocytes, and compound 5-2 is less cytotoxic to human hepatocyte co-cultures than sofosbuvir.
Reported figures show that representative compounds reduce HCV replication.
Documented Applications
Treatment of hepatitis C in a host in need thereof, including a human host, by administering an anti-HCV effective amount of the claimed compound or a pharmaceutically acceptable salt thereof.
Prophylaxis of HCV infection and use in combination therapy with other antivirals.
Oral administration in tablet or capsule dosage forms.
Interested in licensing this patent?