Non-Nucleoside Reverse Transcriptase Inhibitors

Inventors: Daniel Elleder, John Young, Thomas Baiga, Joseph Noel
Potential Uses: HIV, Infection, Virus, Drug Development
Novel NNRTIs, compounds and pharmaceutical compositions for reducing HIV infection and replication.

Resistance of the human immunodeficiency virus (HIV) to HIV drugs has always been a major cause of treatment failure, leading to the use of combination therapy employing multiple anti-HIV agents, each usually having a different activity profile.

The introduction of HAART therapy (Highly Active Anti-Retroviral Therapy), for example, has resulted in a significant reduction of morbidity and mortality in those HIV patients receiving it. HAART involves various combinations of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). Current guidelines for antiretroviral therapy now recommend triple combination therapy regimens for initial treatment.

Unfortunately, multi-drug therapies do not completely eliminate HIV, and long-term treatment usually results in multi-drug resistance. Half of the patients receiving anti-HIV combination therapy fail to respond fully, mainly because of resistance of the virus to one or more drugs used. The resistant virus is also carried over to newly infected individuals, who as a result have severely limited therapy options.

Recently Salk Institute scientists identified a novel lead compound: a non-nucleoside reverse transcriptase inhibitor (NNTRI) that substantially reduces the activity of HIV-1 reverse transcriptase, thereby reducing HIV infection. This NNTRI also acts synergistically with one particular NRTI, zidovudine (or AZT), the first drug approved for the treatment of HIV.

Structural Activity Relationship (SAR) analysis has identified additional, more potent derivatives of this compound, and experiments have confirmed their efficacy against wild-type and existing drug-resistant HIV-1 variants isolated from patients. The technology disclosed in the pending patent includes novel NNRTIs and compounds that can substantially inhibit HIV infection and replication and can be used in combination with other retriviral inhibitors. Also described are pharmaceutical compositions, prodrugs of the compounds, and methods for their creation, preparation and use.