PHOSPHOANIONIC DELIVERY OF ANTIAIDS & DRUG ABUSE ANTAGONISTS

相当数量的艾滋病和艾滋病-痴呆患者在中枢神经系统/大脑中出现由人类免疫缺陷病毒（HIV）引起的神经系统并发症。因此，至关重要的是，艾滋病药物穿透血脑屏障（BBB），抑制HIV复制，以减轻中枢神经系统功能障碍。然而，在血脑屏障处，由于药物的亲脂性不足，艾滋病药物如3'-azidothymidine (AZT), 2',3'-dideoxycytidine （DDC）的摄取非常低。即使某些药物穿透脑屏障，大脑中的药物浓度也可能不足以阻止HIV复制，一旦进入中枢神经系统/大脑，由于其极性和可电离官能团，这些药物的半衰期也很低。因此，我们假设这些艾滋病药物与亲脂剂或亲脂性中枢神经系统药物通过“磷酸盐”或“膦酸盐”键的化学掩膜可能产生磷酸盐/膦酸盐阴离子递送剂（ADA），由于其高亲脂性，ADA可以很容易地穿透BB，并在一段时间内将具有生物活性的母体药物缓慢释放到中枢神经系统/大脑中。因此，该研究旨在设计、合成和评估选定的艾滋病和药物滥用治疗剂的“磷酸盐”和“膦酸盐”型阴离子药物递送剂，以增强细胞递送、保留和进入脑/中枢神经系统的治疗效率，以治疗脑疾病，如艾滋病、艾滋病痴呆和药物滥用。“磷酸盐”和“膦酸盐”型阴离子药物递送剂将包括几种酰基烷基，烷基和芳基磷酸和膦酸二酯和/或三酯的艾滋病前药和药物滥用治疗剂，目前正在使用或正在研究用于治疗中枢神经系统相关疾病。随后，将对这些试剂进行完整的体外水解评价。体内脑摄取研究也将在Sprague Dawley大鼠中进行，以评估选定的磷酸盐/膦酸盐药物进入中枢神经系统的增强递送的潜力。这些研究的结果有望为极性和可电离药物向中枢神经系统/大脑的输送提供有价值的概念信息。(鉴于项目周期由5年改为3年，我们在修订后的建议中减少了建议的化合物数目。具体目标部分给出了具体变化的摘要。)

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.)