A series of compounds that are either homodimers or heterodimers of specific dideoxynucleosides have been synthesized. In various assays, the phosphate-linked dimers of such antiviral monomeric dideoxynucleosides possess greater activity than the combined activity of the dideoxynucleosides administered alone. Preliminary pharmacokinetic data obtained for one of the agents after intravenous administration to rats indicated that it crossed the blood-brain barrier with a distribution that compared favorably to AZT. It is planned to expand the series of dimeric compounds by synthesizing drugs that include the following nucleosides: ddA, ddI, ddC, ddG, and AZT. Since the lipophilicity and, therefore, the CNS bioavailability of the specific agents appears to be greater for the esterified analog of the nucleoside dimer triester, a series of triesters will be prepared to examine the impact of such substitution on antiviral activity and cytotoxicity. Based on the in vitro results that are obtained, the in vivo distribution and metabolism of the most active compounds will be examined. The information obtained from these experiments will lead to the choice of specific compounds to be studied in Phase II.
Anticipated Results:AZT, the only anti-HIV agent currently approved by the Food and Drug Administration, is associated with several unwanted side effects. A strategy to overcome this problem is to use combinations of effective drugs. The dimeric compounds to be synthesized will combine effective nucleoside agents to enhance their anti-HIV effects and decrease their cytotoxic properties.National Institute of Allergy And Infectious Diseases
