Tropolone compounds for treating or preventing retroviral infection
Inventors
Beutler, John A. • LeGrice, Stuart F. J. • Thomas, Craig • Jiang, Jian-Kang • Chung, Suhman • Wilson, Jennifer
Assignees
US Department of Health and Human Services
Publication Number
US-8993768-B2
Publication Date
2015-03-31
Expiration Date
2032-05-10
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Disclosed are compounds that inhibit RNase H activity of retroviruses, for example, a compound of formula (I) wherein R1, R2, and R3 are as described herein, as well as pharmaceutically acceptable salts, solvates, stereoisomers, and prodrugs thereof. Pharmaceutical compositions comprising such compounds, as well as methods of use, and treatment or prevention of infection by human immunodeficiency virus (HIV).
Core Innovation
The invention provides compounds that inhibit the RNase H activity of retroviruses, particularly HIV, using compounds of formula I with various substituents R1, R2, and R3. These compounds and their pharmaceutically acceptable salts, solvates, stereoisomers, and prodrugs form pharmaceutical compositions for treatment or prevention of retroviral infection, specifically HIV.
The problem addressed is the need for improved treatments for HIV infection by developing new retroviral RNase H inhibitors. Existing inhibitors like the natural product manicol potently inhibit RNase H, but show no reduction in virus replication in culture, likely due to toxicity from inhibition of cellular enzymes. There are concerns about toxicity, selectivity, and cellular penetration with previously reported small molecule inhibitors of RNase H, and a lack of effective clinical data.
Claims Coverage
The patent contains multiple claims covering compounds of formula I and their derivatives, pharmaceutical compositions containing these compounds, and methods of treating retroviral infections by administering these compounds. The main inventive features relate to the compounds’ chemical structure, pharmaceutical compositions, combination with other antivirals, and methods of use for inhibiting HIV and RNase H activity.
Compounds of formula I with specified substituents
Compounds having the general Formula I with R1 selected from a broad group including heterocyclyl C1-C6 alkyl, (di)alkylamino alkyl, aryl alkylamino, alkylthio and related groups, with optional substitutions; R2 as H, OH, or C1-C3 alkyl; and R3 as C1-C6 alkyl, including pharmaceutically acceptable salts, solvates, stereoisomers, and prodrugs.
Pharmaceutical compositions containing the compounds
Pharmaceutical compositions comprising at least one compound of formula I or its salt, solvate, stereoisomer, or prodrug along with a pharmaceutically acceptable carrier.
Pharmaceutical compositions combined with other antiviral compounds
Pharmaceutical compositions comprising at least one compound of formula I and one or more other antiviral compounds, such as nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), integrase inhibitors, fusion inhibitors, or protease inhibitors, together with a pharmaceutically acceptable carrier.
Methods of treating or preventing retroviral infection
Methods involving administering an effective amount of at least one compound of formula I or its salt, solvate, stereoisomer, or prodrug to a subject to treat or prevent retroviral infection.
Methods of inhibiting HIV replication and RNase H activity
Methods of inhibiting HIV replication in a subject or host cell by administering or contacting with an effective amount of at least one compound of formula I or its derivatives; similarly, methods of inhibiting RNaseH activity of HIV in infected subjects or host cells.
The claims collectively cover the chemical structures of novel tropolone-based RNase H inhibitors, their pharmaceutical formulations alone or in combination with other antiviral agents, and their therapeutic use in preventing and treating retroviral infections, specifically HIV, by inhibiting viral replication and RNaseH activity.
Stated Advantages
The compounds inhibit RNase H activity of HIV retrovirus effectively.
The compounds provide reduced cytotoxicity compared to the natural product manicol.
Some compounds exhibit improved specificity for RNase H active site over DNA polymerase activity.
Documented Applications
Treatment or prevention of retroviral infections, including HIV infection.
Inhibition of HIV replication in infected subjects or host cells.
Use in pharmaceutical compositions alone or in combination with other antiviral drugs such as NRTIs, NNRTIs, integrase inhibitors, fusion inhibitors, and protease inhibitors.
Interested in licensing this patent?