AZIDE TECHNOLOGY FOR DRUG DEVELOPMENT

Recently, Professor David C. K. Chu of the University of Georgia, Professor Raymond F. Schinazi of Emory University and colleagues reported that 6-azidopurine arabinoside can be reduced by NADPH- cytochrome P450 reductase to adenine arabinoside (arabinosyl adenine, ara-A or Vidarabine). As a result, the azidopurine nucleoside can act as a slow releaser of the active antiviral drug with very favorable plasma half-life, tissue distribution and pharmacokinetics. On the basis of their promising preliminary results and their strong proprietary position, Pharmasset licensed this technology from Emory University and the University of Georgia. We plan to explore this technology to improve efficacy of certain drugs currently used clinically, or to make those that have shown excellent biological activity, but could not be used in clinic due to their metabolic instability or solubility problems, clinically usable agents. In Phase I, we will synthesize three new 6-azidopurine derivatives as prodrugs of clinically used antiviral agents, Acyclovir, ganciclovir and penciclovir, and three novel nucleosides containing the azide group at the 6 position of the purine ring as prodrugs of ara-G, cordycepin and Cladribine. Ara-G and cordycepin have exhibited potent antineoplastic activity, but ara-G is too insoluble in aqueous medium and cordycepin is very rapidly inactivated by deamination. Cladribine is a clinical drug, but it requires intravenous infusion. The new azide prodrugs of these clinically important drugs will be evaluated for their anticancer and antiviral activities. In collaboration with Professor F. D. Boudinot of the University of Georgia, the bioavailability and tissue distribution of the new compounds will be studied. In Phase II, we will select one or two of the most promising compounds, and prepare larger amounts for preclinical toxicological and pharmacological studies required for an IND application PROPOSED COMMERCIAL APPLICATIONS: There are many biologically active compounds, but their metabolic instability or solubility problems limits their clinical use. Our technology would overcome some of their limitations, which will lead to the development of highly useful clinical drugs. For example, Cladribine, a clinical drug that requires intravenous infusion, will be developed as an orally bioavailable prodrug. If our Phase I studies lead to drugs with improved pharmacology, their commercial potential will be very high.