Betulinol derivatives as anti-HIV agents

Abstract

The present invention relates to methods of treating HIV-1 infection in a subject. These methods involve administering to the subject with HIV-1 infection a therapeutically effective amount of a conjugated or immunoconjugated betulinol derivative compound, or a pharmaceutically acceptable salt or derivative thereof, under conditions effective to treat the subject for HIV-1 infection. Also disclosed are methods inhibiting HIV-1 activity in a cell. These methods involve providing a cell infected with HIV-1 and contacting the cell with a conjugated or immunoconjugated betulinol derivative compound, or a pharmaceutically acceptable salt or derivative thereof, under conditions effective to inhibit HIV-1 activity in the cell.

Description

[0001] This application claims the priority benefit of U.S. Provisional Patent Application Ser. No. 60 / 609,080, filed Sep. 10, 2004, U.S. Provisional Patent Application Ser. No. 60 / 630,103, filed Nov. 22, 2004, and U.S. Provisional Patent Application Ser. No. 60 / 630,150, filed Nov. 22, 2004, which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION [0002] The present invention relates generally to methods of treating HIV-1 infection in a subject and methods of inhibiting HIV-1 activity in a cell using betulinol derivative compounds. BACKGROUND OF THE INVENTION [0003] Human Immunodeficiency Virus (“HIV”), the virus that causes AIDS, has reached pandemic proportions in the world. Some one million people are infected with HIV in the U.S. alone, and more than forty million worldwide. Each day, approximately 12,000 adults and 1,800 children become infected. Currently, there are three classes of drug treatments for HIV, namely, reverse transcriptase (“RT”) inhibi...

AI Technical Summary

Benefits of technology

[0152] While the prior art discloses a number of different betulinol derivatives having antiviral activity, the betulinol derivatives of the present invention are particularly effective against Human Immunodeficiency Virus and, in particular, HIV-1. Moreover, the betulinol deriva

Problems solved by technology

However, these currently acceptable treatment drugs are limited by either their toxicity or the emergence of drug-resistant HIV strains (Evers et al., J. Med. Chem. 39:1056-1063 (1996)).

In addition, these drugs are costly, difficult to manufacture, and have adverse side effects.

Unfortunately, however, many of these betulinol derivative compounds have significant drawbacks to their use.

In addition, no current anti-HIV agent, with the exception of α-interferon, has any effect on release of virus from a chronically infected cell.

However, betulonic acid and the known betulinol derivatives are generally insoluble in aqueous environment or other pharmaceutically acceptable solvents.

Absent this property, administration of the pharmaceutical agent to mammals can be difficult and biological activity in such mammals (including humans) may be impeded or entirely absent.

Due to their limited solubility in aqueous solutions, the use of terpenoids such as betulinol and it derivatives as pharmaceuticals has been limited.

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