Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections
Inventors
Gavegnano, Christina • Schinazi, Raymond F
Assignees
Emory University • US Department of Veterans Affairs
Publication Number
US-11744831-B2
Publication Date
2023-09-05
Expiration Date
2032-11-30
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Abstract
Compounds, compositions, and methods of treatment and prevention of Hepacivirus, Pestivirus, Flavivirus or Alphavirus infection are disclosed. The compounds are pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidine JAK inhibitors. Combinations of these JAK inhibitors and additional antiretroviral compounds, such as NRTI, NNRTI, integrase inhibitors, entry inhibitors, protease inhibitors, and the like, are also disclosed. In one embodiment, the combinations include a combination of adenine, cytosine, thymidine, and guanine nucleoside antiviral agents, optionally in further combination with at least one additional antiviral agent that works via a different mechanism than a nucleoside analog. This combination has the potential to eliminate the presence of Hepacivirus, Pestivirus, Flavivirus or Alphavirus in an infected patient.
Core Innovation
The invention provides compounds, compositions, and methods for the treatment and prevention of infections caused by Hepacivirus, Pestivirus, Flavivirus or Alphavirus. The compounds are pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidine JAK inhibitors, including several specific chemical formulae and exemplified by compounds such as Ruxolitinib and Tofacitinib.
The invention addresses the problem of drug resistance and toxicity associated with current antiviral therapies for HIV-1 and related viral infections. Existing therapies, including nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors, integrase inhibitors and others, can lead to emergence of resistant viral strains and often require long-term administration without achieving a cure. The invention provides JAK inhibitors that act via mechanisms not associated with resistance development, and can be used alone or in combination with other antiviral agents to enhance efficacy and reduce toxicity.
Claims Coverage
The patent contains independent claims directed to methods of treating specific viral infections using compounds of Formula A and selected JAK inhibitors, as well as compositions combining these inhibitors with other antiviral agents. The main inventive features focus on the use of defined JAK inhibitors and their chemical structures for treating various infections.
Method for treating viral infections with compounds of Formula A
A method for treating a Hepacivirus, Pestivirus, Flavivirus or Alphavirus infection by administering to a patient an effective amount of a compound of Formula A, which includes a detailed chemical structure with specified substituents and variations.
Method for treating viral infections with selected JAK inhibitors
A method for treating a Hepacivirus, Pestivirus, Flavivirus or Alphavirus infection by administering an effective antiviral amount of selected JAK inhibitors from a specified group, including named inhibitors such as CEP-701, AZD1480, and Tofacitinib, as well as particular chemical compounds and their pharmaceutically acceptable salts and prodrugs.
Combination therapy with JAK inhibitors and additional antiviral agents
A method that further comprises co-administration of at least one additional antiviral agent selected from non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors, fusion inhibitors, entry inhibitors, attachment inhibitors, and integrase inhibitors, together with the compound of Formula A for enhanced antiviral therapy.
Defined chemical structure of compounds of Formula A
The compound of Formula A is specified with precise chemical structural formulae detailing the arrangement of rings, functional groups, and substituents that characterize this class of antiviral JAK inhibitors.
Defined chemical structure of compounds of Formula B
Compound of Formula B is provided with detailed chemical structure specifications including heteroatoms, ring systems, and substituents that outline another class of JAK inhibitors applicable for treatment of viral infections.
The claims establish the novel use of defined JAK inhibitors, especially compounds of Formula A and specified JAK inhibitor groups, for treatment of Hepacivirus, Pestivirus, Flavivirus or Alphavirus infections including compositions optionally combined with other antiviral agents to improve efficacy and mitigate resistance.
Stated Advantages
JAK inhibitors demonstrate potent antiviral activity with a wide therapeutic window and minimal cytotoxicity compared to existing agents like AZT and 3TC.
The combination of JAK inhibitors with nucleoside antiviral agents minimizes the emergence of viral resistance by attacking the virus through multiple mechanisms.
JAK inhibitors can inhibit HIV reactivation from latency, reducing the viral reservoir and potentially leading to virus eradication.
Certain JAK inhibitors also inhibit CYP3A4, enhancing plasma levels of co-administered anti-HIV drugs.
The invention provides means for synergistic therapy that can reduce required doses of individual drugs, thereby reducing toxicity and improving overall antiviral effect.
Documented Applications
Treatment and prevention of viral infections including Hepacivirus, Pestivirus, Flavivirus, and Alphavirus infections such as HIV-1, HIV-2, HCV, Dengue virus, Japanese encephalitis virus, West Nile Virus, Yellow Fever virus, and Chikungunya virus.
Combination or alternation therapy with JAK inhibitors and other antiviral drugs including nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, entry inhibitors, attachment inhibitors, and integrase inhibitors.
Use of JAK inhibitors for reducing HIV reservoir size, inhibiting viral reactivation, and preventing viral rebound in human patients.
Use in combination with macrophage depleting agents, histone deacetylase inhibitors, interleukin 7, vaccines, immunomodulatory agents, and various immunostimulants to enhance antiviral efficacy and potentially cure viral infections.
Pharmaceutical formulation of the compounds for oral, parenteral, and controlled release administration to achieve therapeutic plasma concentrations.
Bioavailability studies in animals and in vitro potency and toxicity assays to support clinical application.
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