Nucleotide analogs
Inventors
Hostetler, Karl Y. • Beadle, James R. • Valiaeva, Nadejda
Assignees
US Department of Veterans Affairs • Office of General Counsel of VA • University of California San Diego UCSD
Publication Number
US-9493493-B2
Publication Date
2016-11-15
Expiration Date
2035-09-15
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Abstract
Disclosed herein, inter alia, are acyclic nucleotide analogs and methods of using an acyclic nucleotide analog for treating and/or ameliorating a papillomavirus infection.
Core Innovation
The invention relates to acyclic nucleotide analogs, specifically to antiviral compounds of Formula (I) and their pharmaceutical compositions and methods of synthesis. These compounds and compositions are designed for treating viral infections, particularly those caused by papillomavirus, including human papillomavirus (HPV). The invention emphasizes inhibition of viral DNA synthesis to block viral replication and production of virions, aiming to prevent progression to invasive cancers caused by high-risk HPV types.
The background identifies the problem as the lack of approved antiviral treatments for early human papillomavirus infections that have not yet progressed to cancer. Papillomaviruses cause conditions such as skin and genital warts, respiratory papillomatosis, and various cancers, notably cervical cancer driven by high-risk HPV types like HPV-16 and HPV-18. Current HPV vaccines are preventative and less effective for already infected individuals. Existing antiviral nucleoside analogs have limitations including poor oral bioavailability and high toxicity. There is a need for effective antiviral agents that selectively inhibit HPV replication without significant cytotoxicity.
The innovation includes compounds which selectively inhibit HPV DNA synthesis with minimal antiproliferative effects on host cells, thereby offering antiviral effects without significantly affecting host cell division. The invention encompasses compounds of Formula (I), pharmaceutically acceptable salts and prodrugs thereof, pharmaceutical formulations containing these compounds, methods for their manufacture, and methods for treating or preventing papillomavirus infections. The compounds can be administered for treating both low-risk and high-risk HPV types, using effective dosages tailored to subject characteristics and formulated for various administration routes.
Claims Coverage
The patent claims encompass four independent claims focused on compounds of Formula (I), pharmaceutical compositions comprising these compounds, and methods of treating human papillomavirus infection using these compounds or compositions.
Compounds of Formula (I) for treating HPV infection
Claims selected groups of compounds defined by Formula (I), which are acyclic nucleotide analogs characterized by specific molecular structures including variations in the nucleotide base, phosphonate moiety, and substituents R1, R2, and others, designed to inhibit viral DNA synthesis of human papillomavirus.
Pharmaceutical compositions containing compounds of Formula (I)
Covers pharmaceutical compositions comprising an effective amount of compounds of Formula (I), including pharmaceutically acceptable salts, combined with carriers suitable for administration to treat HPV infections.
Methods of treating human papillomavirus infection by administering compounds of Formula (I)
Describes methods of treating a host infected with HPV by administering an effective amount of compounds of Formula (I) or their pharmaceutically acceptable salts, optionally formulated in pharmaceutically acceptable carriers, to inhibit viral replication by blocking viral DNA synthesis.
Use of compounds of Formula (I) in medicament manufacture
Claims use of compounds of Formula (I) or their salts in the manufacture of medicaments intended for treatment or prevention of papillomavirus infections by inhibiting viral DNA replication.
The independent claims collectively cover novel compounds of Formula (I), their pharmaceutical formulations, methods of treatment involving administration of these compounds to inhibit HPV replication by blocking viral DNA synthesis, and their use in medicament manufacturing, thereby addressing the lack of effective antiviral therapies for HPV infections.
Stated Advantages
The antiviral agents selectively inhibit HPV replication and viral DNA synthesis without significant antiproliferative effects on host cells.
These agents can eradicate papillomavirus infection before progression to invasive cancers, representing a therapeutic advance over existing treatments.
The compounds exhibit improved oral bioavailability, increased cellular membrane penetration, and enhanced stability by neutralizing the phosphonate charge with specific moieties.
The prodrug forms moderate the release of the active metabolite, maintaining efficacy while reducing toxicity and undesirable effects.
Documented Applications
Treatment and amelioration of human papillomavirus infections, including both high-risk types such as HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-68, HPV-73, HPV-82 and low-risk types such as HPV-6 and HPV-11.
Use of compounds of Formula (I) in pharmaceutical compositions for treating or preventing papillomavirus infections.
Use in manufacturing medicaments aimed at inhibiting viral DNA synthesis to prevent disease progression associated with HPV infection.
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