Discovery of Novel Inhibitors of HIV-1 Integrase and/or RNase H That Can Be Used for the Treatment of Retroviral Infection Including AIDS


This invention provides compounds and methods of treating retroviral infection such as AIDS by administration of a dioxtetrahydrobenzo[a]naphthacene compound, particularly a 8,13-dioxo-5,6,8,13-tetrahydro-benzo[a]naphthacene compound, i.e. a madurahydroxylactone compound. Retroviruses, such as HIV, need three viral enzymes for replication: reverse transcriptase, protease, and integrase. The prognosis of AIDS patients has recently been improved by the discovery and associated therapeutic administration of reverse transcriptase and/or protease inhibitors. However, a significant portion of AIDS patients fail to respond to such treatments and viral resistance remains a major problems.

It is known that HIV-1 integrase is a rational target for AIDS therapy because genetic studies have demonstrated that the enzyme is essential for viral replication, and because there is no cellular equivalent. On the other hand, the reverse transcriptase RNase H active site is another good target for antiviral therapeutic development because elimination of the RNase H activity of reverse transcriptase arrests virus replication. The compounds reported in this invention may be capable of inhibiting both enzymes since the catalytic centers of integrase and RNase H are structurally similar. As a consequence, this invention can potentially avoid viral resistance, which limits the efficacy of presently administered reverse transcriptase and/or protease inhibitor therapeutic agents. Thus, the invention may be a group of new small molecule agents for treating patients suffering from retroviral infections, particularly patients suffering from Human Immunodeficiency Virus (HIV).



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OTT Reference No: E-022-2003/0
Updated: Dec 1, 2003