Central nervous system (CNS) HIV infections can cause severe problems such as AIDS-related dementia. The brain, however, excludes many active anti-HIV drugs because of the blood brain-barrier (BBB). The objective of this project is the design, synthesis and anti-HIV evaluation of prodrugs with improved CNS transport properties. F-ddA, a LMCH drug in the final stages of a NCI Phase I clinical trial, is being used as a prototype prodrug in an evolving mathematical model designed to choose an optimum CNS candidate from among a group of 16 new compounds synthesized for that purpose. These compounds can be enzymatically hydrolyzed by adenosine deaminase (ADA) to F-ddI, an anti-HIV-active compound. Compound properties (lipophilicity, acid-stability) determine BBB penetration, with ADA-catalyzed hydrolysis in the CNS generating the active material (F-ddI). Rat tissue distribution data for these compounds are being generated for correlation with compound properties in a physiologic-based mathematical model. In addition, more efficient methods for 2'-fluoronucleoside synthesis are being investigated based on newly discovered chemistry. AIDS title:""""""""Fluoronucleosides as CNS-Targeted Anti-Aids Drugs""""""""

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010000-04
Application #
6289275
Study Section
Special Emphasis Panel (LMC)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code