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-9089574-B2
Publication Date
2015-07-28
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 relates to 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. These JAK inhibitors can be used alone or in combination with additional antiretroviral compounds such as NRTI, NNRTI, integrase inhibitors, entry inhibitors, and protease inhibitors. The combination therapy, including adenine, cytosine, thymidine, and guanine nucleoside antiviral agents, optionally with additional agents working via different mechanisms, potentially eliminates HIV in infected patients.
The problem being solved is the lack of an effective cure for HIV-1 infection and AIDS despite the availability of triple drug HAART therapies. These therapies reduce mortality and disease progression but do not eliminate HIV-1 and often lead to multidrug resistance. Current drugs are toxic and require complicated dosing, resulting in poor compliance. There is a need for additional drugs and treatment regimens that minimize virological failure, circumvent viral resistance, reduce toxicity, and offer a possible cure by destroying the virus in all reservoirs.
The invention provides antiretroviral JAK inhibitors and their use alone or in combination with nucleoside analogs representing all four bases (ACTG) and/or other antiviral agents to suppress HIV infection effectively. The JAK inhibitors function in a manner unlikely to provoke resistance as it does not inhibit viral enzymes or cause enzyme mutations. Combination with multiple nucleosides and additional agents creates multiple pressures on the virus, preventing adaptation and resistance and allowing thorough chain termination in viral DNA polymerization.
Claims Coverage
The patent includes multiple independent claims covering methods of treating HIV infections using JAK inhibitor compounds of Formula A and compositions comprising these compounds, alone or in combination with other antiviral agents or therapies.
Method for treating an HIV infection with JAK inhibitor compounds of Formula A
Administering to a patient an effective antiviral amount of a compound of Formula A for treating HIV infection.
Combination therapy with nucleoside and additional antiviral agents
Co-administration of (a) at least one each of adenine, cytosine, thymidine and guanine nucleoside antiviral agents, or (b) at least one additional antiviral agent selected from NNRTIs, protease inhibitors, fusion inhibitors, entry inhibitors, attachment inhibitors, and integrase inhibitors.
Combination of HAART and JAK inhibitor with macrophage depletion or reactivation agents
Methods involving reducing viral loads by administering HAART and JAK inhibitors of Formula A combined with macrophage depleting agents (e.g., Boniva or Fosamax) or reactivation agents such as panobinostat to treat or eradicate HIV infection.
Method for treating viral diseases with JAK inhibitor compounds
Administering effective antiviral amounts of JAK inhibitor compounds of Formula A for treating viral diseases, optionally in combination or alternation with second antiviral agents such as interferons, ribavirin, protease inhibitors, polymerase inhibitors, helicase inhibitors, and other listed antiviral agents.
Pharmaceutical compositions combining JAK inhibitors and additional antiviral agents
Compositions comprising JAK inhibitors of Formula A or B combined with at least one nucleoside antiviral agent covering all four bases (ACTG) and/or other antiviral agents such as NNRTIs, protease inhibitors, integrase inhibitors and fusion inhibitors, administered in combination or alternation.
Methods and compositions including a broad list of specific JAK inhibitors
Methods and compositions incorporating a broad grouping of specific JAK inhibitors, including Jakafi, Tofacitinib, LY3009104/INCB28050, CEP-701, AZD1480, Lestaurtinib and other named compounds, and their pharmaceutically acceptable salts and prodrugs.
The claims cover methods for treating HIV infections via administration of JAK inhibitors of Formula A, alone or combined with various nucleoside antiviral agents and other antiretroviral compounds, including combinations with HAART and agents that deplete macrophages or reactivate latent virus. The claims also cover pharmaceutical compositions with these combinations and a broad range of JAK inhibitor compounds for viral diseases.
Stated Advantages
The antiviral combinations reduce the effective dose required, thereby reducing toxicity.
They improve the absolute antiviral effect due to synergistic multiple mechanisms of attack on the virus.
Use of JAK inhibitors provides a way to circumvent the development of viral resistance.
Combination therapy minimizes the virus's ability to develop resistance to nucleoside antiviral agents.
JAK inhibitors do not provoke resistance since they act intracellularly without directly interfering with viral replication enzymes.
Documented Applications
Treatment and prevention of HIV infection, including HIV-1, HIV-2, and drug-resistant strains.
Combination therapy for HIV to achieve potential eradication of virus from all reservoirs.
Treatment or prevention of Flaviviridae infections including Hepatitis C virus (HCV), Bovine Viral Diarrhea Virus (BVDV), Classical Swine Fever Virus (CSFV), Border Disease Virus (BDV), Dengue virus, Japanese encephalitis virus group (including West Nile virus), Yellow Fever virus.
Treatment of Alphaviruses such as the Chikungunya virus.
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