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-10022378-B2
Publication Date
2018-07-17
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 treatment and prevention of HIV infection. These compounds are pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidine Janus kinase (JAK) inhibitors. The methods include the use of these JAK inhibitors alone or in combination with additional antiretroviral compounds such as nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), integrase inhibitors, entry inhibitors, protease inhibitors, and others. Combination therapies involving adenine, cytosine, thymidine, and guanine nucleoside antiviral agents with other antiviral agents working via different mechanisms are also disclosed to potentially eliminate HIV in infected patients.
The background highlights that current HIV treatments, including HAART which combines multiple drug classes, reduce disease progression but do not eliminate HIV infection. Long-term treatment often leads to multidrug resistance and toxicity, requiring development of additional therapies. Drug-resistant HIV variants commonly emerge due to mutations in viral enzymes facilitating replication. Combination/alternation therapies exist to prolong drug efficacy but do not provide a cure.
The invention addresses the need for combination therapies that overcome virological failure and can potentially cure HIV/AIDS by eliminating virus from all reservoirs. Specifically, the antiretroviral JAK inhibitors described act in a distinct intracellular manner, with a mechanism unlikely to provoke resistance. Combinations comprising JAK inhibitors and nucleoside antiviral agents corresponding to all viral bases (ACTG) minimize viral resistance development and more thoroughly terminate viral DNA chain elongation. Additional therapeutic agents with different modes of action, such as cytokines or viral mutagenic agents, can be combined with JAK inhibitors and nucleosides to enhance efficacy.
Claims Coverage
The patent includes 25 claims with multiple inventive features related to methods for treating HIV infection and pharmaceutical compositions containing specific compounds. Key inventive features focus on compounds of Formula A, combination therapies involving antiviral agents, and adjunct agents like macrophage depleting agents and vaccines.
Method of treating HIV infection with compounds of Formula A
Administering an effective antiviral amount of a compound of Formula A to a patient in need to treat HIV infection.
Co-administration of nucleoside antiviral agents or additional antiviral agents
The method further includes co-administration of at least one each of adenine, cytosine, thymidine, and guanine nucleoside antiviral agents, or at least one additional antiviral agent chosen from NNRTIs, protease inhibitors, fusion inhibitors, entry inhibitors, attachment inhibitors, and integrase inhibitors.
Combination therapy including macrophage depleting agents
The method further comprises co-administration of a macrophage depleting agent such as Boniva or Fosamax, optionally with HAART and compounds of Formula A.
Combination therapy with JAK inhibitors and HAART to reduce viral load
Reducing viral loads by administering a combination of HAART and a JAK inhibitor of Formula A.
Combination therapy including reactivation agents
Using a combination including a JAK inhibitor of Formula A and a reactivation agent like panobinostat to treat or eradicate HIV infection.
Combination therapy comprising anti-HIV vaccines or immunostimulatory agents
Further comprising administering an anti-HIV vaccine and/or immunostimulatory agent before, during, or after treatment with a compound of Formula A, optionally together with HAART.
Pharmaceutical compositions containing compounds of Formula A and additional antiviral agents
Pharmaceutical compositions comprising a compound of Formula A, optionally with at least one each of adenine, cytosine, thymidine, and guanine nucleoside antiviral agents, or additional antiviral agents such as NNRTI, protease inhibitors, fusion inhibitors, entry inhibitors, attachment inhibitors, and integrase inhibitors.
The claims cover therapeutic methods employing compounds of Formula A for HIV infection, either alone or in combination with multiple classes of antiviral agents, macrophage depleting agents, reactivation agents, vaccines, and immunostimulants. Pharmaceutical compositions containing these compounds with other antiviral agents and adjunct therapies are also claimed, establishing a broad treatment strategy for HIV infection and eradication.
Stated Advantages
The antiviral combinations minimize the effective dose required of individual drugs, thereby reducing toxicity.
The combinations improve absolute antiviral effect by attacking the virus through multiple mechanisms.
The use of JAK inhibitors circumvents the development of viral resistance, resulting in more efficacious treatment.
Therapies have the potential to treat drug-resistant HIV strains and reduce or prevent viral rebound.
JAK inhibitors show a large therapeutic window with potent inhibition of viral replication and low cytotoxicity.
Use of combination therapy including JAK inhibitors and nucleoside agents may potentially eliminate HIV infection, especially when administered in early stages.
Documented Applications
Treatment and prevention of HIV-1 and HIV-2 infections, including methods to eradicate or cure HIV infection.
Combination therapies comprising JAK inhibitors, nucleoside antiviral agents corresponding to adenine, cytosine, thymidine, and guanine bases, and additional antiviral agents such as NNRTIs, protease inhibitors, entry inhibitors, fusion inhibitors, attachment inhibitors, and integrase inhibitors.
Use in patients infected with drug-resistant HIV strains having specific mutations such as M184V, K65R, or thymidine analog mutations.
Combination therapy including macrophage depleting agents (e.g., Boniva, Fosamax) with HAART and JAK inhibitors to eradicate HIV reservoirs.
Combination therapy with histone deacetylase inhibitors or interleukin-7 and HAART with JAK inhibitors to reactivate and clear latent HIV infection.
Administration along with anti-HIV vaccines and/or immunostimulatory agents to enhance immune response in infected patients.
Treatment and prevention of other viral infections including infections caused by Flaviviridae such as Hepatitis C virus, Dengue virus, West Nile virus, Yellow fever virus, Pestivirus genus members, and Alphaviruses such as Chikungunya virus.
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