Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections
Inventors
Gavegnano, Christina • Schinazi, Raymond F.
Assignees
US Department of Veterans Affairs
Publication Number
US-9662332-B2
Publication Date
2017-05-30
Expiration Date
2032-11-30
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Abstract
Compounds, compositions, and methods of treatment and prevention of HIV 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 HIV in an infected patient.
Core Innovation
The invention provides compounds, compositions, and methods of treatment and prevention of HIV infection using pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidine JAK inhibitors, either alone or in combination with additional antiretroviral compounds such as NRTI, NNRTI, integrase inhibitors, entry inhibitors, and protease inhibitors. It also encompasses combinations including adenine, cytosine, thymidine, and guanine nucleoside antiviral agents, optionally combined with at least one additional antiviral agent operating via a different mechanism than nucleoside analogs, aiming to eliminate HIV presence in infected patients.
The problem addressed is the emergence of drug-resistant HIV-1 strains following prolonged treatment with conventional antiviral agents, including mutations in reverse transcriptase, protease, or DNA polymerase genes. Current therapies like HAART, though effective in reducing mortality and disease progression, do not eliminate the virus, often lead to multidrug resistance, and have toxic side effects or complicated dosing schedules that impact compliance and efficacy. There is a continuous need for novel treatments that minimize virological failure and potentially cure HIV/AIDS by eradicating the virus from all reservoirs.
The invention uniquely employs JAK inhibitors that function intracellularly in a manner distinct from conventional antiretroviral therapies, and thus are less likely to provoke resistance. When combined with nucleoside agents representing all four bases (adenine, cytosine, thymidine, and guanine) and additional antiviral agents, the combination therapy imposes multiple pressures on HIV, reducing viral adaptability and resistance development. Furthermore, this multi-pronged approach targets the polymerase active site through different bases ensuring thorough chain termination, and inclusion of NNRTIs enhances effectiveness by inducing conformational changes in polymerase to prevent chain elongation.
Claims Coverage
The claims include 20 inventive features focusing on methods of treating HIV infection using specified JAK inhibitors individually or in combination with antiviral agents, and pharmaceutical compositions thereof.
Use of specific JAK inhibitors to treat HIV infection
Methods for treating HIV infection by administering effective antiviral amounts of JAK inhibitors selected from Jakafi and others such as LY3009104/INCB28050, Pacritinib/SB1518, VX-509, GLPG0634, INC424, R-348, CYT387, TG 10138, AEG 3482, including pharmaceutically acceptable salts and prodrugs.
Co-administration of nucleoside antiviral agents or other antiviral agents with JAK inhibitors
Methods comprising co-administration with at least one each of adenine, cytosine, thymidine, and guanine nucleoside antiviral agents, or additional antiviral agents including NNRTIs, protease inhibitors, fusion inhibitors, entry inhibitors, attachment inhibitors, and integrase inhibitors.
Co-administration of macrophage depleting agents
Methods wherein JAK inhibitors are administered in combination with macrophage depleting agents to enhance treatment efficacy.
Combination of JAK inhibitors with HAART therapy
Methods combining JAK inhibitors with HAART to reduce viral loads, including stepwise macrophage depletion while maintaining HAART and JAK inhibitors, then measured withdrawal of macrophage depleting agents and eventual withdrawal of HAART and/or JAK inhibitors optionally monitoring viral rebound.
Combination with reactivation agents
Methods including administration of reactivation agents during HAART and JAK inhibitor therapy, withdrawal of reactivation agents upon increased viral loads, continuation of HAART and JAK inhibitors until sustained low viremia, followed by withdrawal of HAART and/or JAK inhibitors with monitoring.
Use with anti-HIV vaccines or immunostimulatory agents
Methods administering JAK inhibitors in combination with HAART plus anti-HIV vaccines or immunostimulatory agents before, during, or after JAK inhibitor administration.
Pharmaceutical compositions containing JAK inhibitors with additional antiviral compounds
Pharmaceutical compositions comprising effective antiviral amounts of specified JAK inhibitors, optionally combined with nucleoside antiviral agents or other antiviral agents such as NNRTIs, protease inhibitors, fusion inhibitors, entry inhibitors, attachment inhibitors, and integrase inhibitors.
Specific antiviral agents in combinations
Compositions including NNRTIs like Sustiva, protease inhibitors like Kaletra, or integrase inhibitors like Raltegravir or Elvitegravir, optionally with anti-HIV vaccines, immunostimulatory agents, macrophage depleting agents such as Boniva or Fosamax, or reactivation agents like panobinostat.
The claims cover therapeutic methods using specified JAK inhibitors alone or combined with multiple classes of antiviral agents or macrophage depleting agents, processes integrating HAART, reactivation agents, vaccines, and immunostimulants, and corresponding pharmaceutical compositions.
Stated Advantages
The antiviral combinations reduce effective doses required, thereby reducing toxicity.
The combinations improve absolute antiviral effect due to multiple mechanisms of viral attack.
Use of JAK inhibitors circumvents development of viral resistance, providing more efficacious treatment.
JAK inhibitors have a large therapeutic window and do not affect viability or proliferation of primary human lymphocytes or macrophages at effective antiviral concentrations.
When combined, the agents exhibit synergistic antiviral effects, enhancing potency against HIV.
Documented Applications
Treatment and prevention of HIV infection, including HIV-1 and HIV-2 infections.
Use in combination with antiretroviral therapies including HAART, macrophage depleting agents, reactivation agents, anti-HIV vaccines, and immunostimulatory agents.
Treatment and prevention of viral infections caused by Flaviviridae, including Hepatitis C virus (HCV), Dengue virus, Japanese encephalitis virus group, West Nile virus, Yellow Fever virus, and Pestiviruses.
Treatment of Alphaviruses such as Chikungunya virus.
Treatment of drug-resistant HIV strains including M184V/I, K65R, and Thymidine analog mutations (TAMS).
Pharmaceutical compositions for treating or preventing viral infections with JAK inhibitors and combinations with nucleoside antiviral agents or other antiviral agents.
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