A significant number of patients with AIDS and AIDS-dementia complex develop neurological complications caused by human immunodeficiency virus (HIV) in the CNS/brain. It is, therefore, critical that the AIDS drug penetrate the blood-brain-barrier (BBB) and suppress the HIV replication in order to alleviate the CNS dysfunction. However, at BBB, the uptake of AIDS drugs such as 3'-azidothymidine (AZT), 2',3'-dideoxycytidine (DDC), is very low due to insufficient lipophilicity of the drugs. Even when some drug seen to penetrate the BB, the drug concentration in the brain may not be adequate to prevent the HIV replication and once inside the CNS/brain, the half life of these drugs is also low due to their polar and ionizable functional groups. Therefore, we hypothesized that a chemical masking of theses AIDS drugs with a lipophilic agent or a lipophilic CNS drug via a 'phosphate' or a 'phosphonate' linkage may produce a phosphate/phosphonate' anionic delivery agent, (ADA) which can readily penetrate the BB on account of its high lipophilicity and slowly release the biologically active parent drug into the CNS/brain over a period of time. The proposed investigation, therefore, seeks to design, synthesize and evaluate 'phosphate' and 'phosphonate' type anionic drug delivery agents of selected AIDS and drug-abuse treatment agents to enhance the cellular delivery, retention, and therapeutic efficiency into the brain/CNS for the treatment of cerebral maladies such as AIDS, AIDS dementia, and drug-abuse. The 'phosphate' and 'phosphonate' type anionic drug delivery agents will include several acyloxyalkyl-, alkyl and aryl phosphate and phosphonate di- and/or tri-esters pro-drugs of AIDS and drug abuse treatment agents currently in use or under investigation for the treatment of CNS-associated maladies. Subsequently, a complete in-vitro hydrolytic evaluation of these agents will e investigated. In vivo brain uptake studies will also be conducted in Sprague Dawley rats to evaluate the potential for the enhanced delivery of selected phosphate/phosphonate agents into the CNS. The outcome of these studies is expected to provide valuable conceptual information for the delivery of polar and ionizable drugs to CNS/brain. (In view of the project period change from 5 to 3 years, we have reduced the number of proposed compounds in this revised proposal. A summary of specific changes is presented in the specific aims section.)
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