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-11065254-B2
Publication Date
2021-07-20
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 for the treatment and prevention of HIV infection using pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidine JAK inhibitors. These inhibitors can be used alone or in combination with other antiretroviral agents such as nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), integrase inhibitors, entry inhibitors, protease inhibitors, and the like. The invention emphasizes combinations that include all four nucleoside antiviral bases (adenine, cytosine, thymidine, and guanine) optionally combined with additional agents that act via mechanisms different from nucleoside analogs, with the potential to eliminate the presence of HIV in an infected patient.
The problem addressed arises from the limitations of current HIV therapies that include HAART (Highly Active Antiretroviral Therapy), which while effective in reducing mortality, do not eliminate HIV and often result in multidrug resistance. Problems include drug-resistant viral mutations, toxicity, complicated dosing schedules, and eventual failure to cure the infection. There is a need for therapies that minimize virological failure, potentially cure HIV/AIDS by destroying the virus in all reservoirs, and provide synergistic treatments that reduce toxicity and the development of resistance.
The invention proposes the use of JAK inhibitors that function by mechanisms distinct from conventional antiretroviral drugs, thereby imposing minimal selective pressure for resistance development. When combined with four nucleoside antiviral agents that cover all nucleotide bases, optionally with additional agents having different viral targets, the therapy achieves thorough chain termination and minimizes viral adaptability. Also disclosed are combinations with macrophage depleting agents, histone deacetylase inhibitors, interleukin 7, vaccines, immunomodulatory agents, and other antiviral agents. The pharmaceutical compositions and methods aim to treat, prevent, and potentially cure HIV by attacking the virus through multiple, synergistic mechanisms.
Claims Coverage
The claims include two independent claims directed to methods of treating or preventing AIDS-related neurological disorders and other AIDS-related conditions using JAK inhibitors with specific chemical structures and compositions.
Use of compounds of Formula A to treat AIDS-related neurological disorders
The method involves administering an effective amount of a compound of Formula A, which encompasses specific pyrrolo[2,3-b]pyrimidine or pyrrolo[2,3-b]pyridine derivatives, or their pharmaceutically acceptable salts or prodrugs, for treatment or prevention of AIDS-related neurological conditions.
Use of selected JAK inhibitors to treat AIDS-related neurological disorders
The method involves administering an effective antiviral amount of specified JAK inhibitors selected from a comprehensive group including CEP-701, AZD1480, LY3009104/INCB28050, Pacritinib, VX-509, GLPG0634, INC424, R-348, CYT387, TG 10138, AEG 3482, and numerous specific pyrrolo[3,2-d]pyrimidin derivatives and pharmaceutically acceptable salts or prodrugs thereof for treatment or prevention of AIDS-related neurological disorders.
Combination therapy with nucleoside antiviral agents or additional antiviral agents
The method further comprises coadministration of either a) at least one each of adenine, cytosine, thymidine, and guanine nucleoside antiviral agents, or b) 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, to enhance treatment efficacy.
Specific coadministered agents for combination therapy
The thymidine nucleoside agent can be zidovudine (AZT), and the nucleoside agents can include (−)-FTC or 3TC, TDF, DAPD or APD, AZT, plus an NNRTI, protease inhibitor, or integrase inhibitor. The NNRTI can be Sustiva, the protease inhibitor Kaletra, and the integrase inhibitor Raltegravir or Elvitegravir.
Administration and formulation details
Compounds of Formula A or B and the coadministered agents can be administered in combination. The method can include coadministration with macrophage depleting agents and is applicable to many AIDS-related conditions such as AIDS-related complex, persistent generalized lymphadenopathy, Kaposi's sarcoma, thrombocytopenia purpurea, and opportunistic infections, using the same classes of compounds as above.
The claims cover methods of treating or preventing AIDS-related neurological disorders and other AIDS conditions using JAK inhibitors of specified chemical formulas, alone or together with combinations of nucleoside antiviral agents and other antiviral drugs. The claims also cover co-administration with macrophage depleting agents and encompass a broad selection of JAK inhibitors and related compounds.
Stated Advantages
The disclosed JAK inhibitors have a wide therapeutic window, exhibiting potent antiviral activity against HIV with minimal cytotoxicity and no significant effect on cell proliferation or viability at effective concentrations.
The combination therapies minimize the emergence of viral resistance by exerting multiple simultaneous pressures on the virus through different mechanisms, and provide synergistic effects that allow lower dosages and reduced toxicity.
The use of JAK inhibitors circumvents resistance mechanisms associated with conventional antiretroviral therapies, potentially extending efficacy in drug-resistant viral strains.
The therapy has the potential, particularly when administered early, to eliminate HIV infection in patients by effectively targeting viral reservoirs and inhibiting reactivation of latent virus.
Documented Applications
Treatment and prevention of HIV-1 and HIV-2 infections, including AIDS-related conditions such as AIDS-related complex, persistent generalized lymphadenopathy, Kaposi's sarcoma, thrombocytopenia purpurea, and opportunistic infections.
Combination therapies including JAK inhibitors and nucleoside antiviral agents (adenine, cytosine, thymidine, guanine nucleosides), NNRTIs, protease inhibitors, integrase inhibitors, fusion inhibitors, entry inhibitors, and attachment inhibitors.
Use in conjunction with macrophage depleting agents, histone deacetylase inhibitors, interleukin 7, vaccines, immunomodulatory agents, and other anti-HIV agents.
Treatment or prevention of other viral infections such as Flaviviridae infections (including Hepatitis C virus, Pestiviruses, and Flaviviruses such as Dengue virus, West Nile virus, Japanese encephalitis virus, Yellow fever virus) and Alphaviruses such as Chikungunya virus.
Therapeutic approaches targeting viral latency, viral reservoir reduction, inflammatory conditions associated with HIV infection, and specific neurological disorders related to AIDS.
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