PHOSPHOANIONIC DELIVERY OF ANTIAIDS & DRUG ABUSE ANTAGONISTS

大量患有AIDS和AIDS-痴呆综合征的患者发展由CNS/脑中的人类免疫缺陷病毒（HIV）引起的神经系统并发症。因此，艾滋病药物穿透血脑屏障（BBB）并抑制HIV复制以减轻CNS功能障碍至关重要。然而，在血脑屏障，艾滋病药物如3 ′-叠氮胸苷（AZT）、2 ′，3 ′-双脱氧胞苷（DDC）的摄取由于药物的亲脂性不足而非常低。即使当一些药物渗透BB时，脑中的药物浓度可能不足以防止HIV复制，并且一旦进入CNS/脑内，这些药物的半衰期也由于其极性和可电离的官能团而较低。因此，我们假设这些AIDS药物与亲脂性试剂或亲脂性CNS药物通过“磷酸盐”或“膦酸盐”键的化学掩蔽可以产生磷酸盐/膦酸盐阴离子递送剂（ADA），其可以由于其高亲脂性而容易地穿透BB，并在一段时间内缓慢地将生物活性母体药物释放到CNS/脑中。因此，所提出的研究试图设计、合成和评价所选AIDS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、保留和治疗效率进入脑/CNS，用于治疗脑疾病，如AIDS、AIDS痴呆和药物滥用。“磷酸盐”和“膦酸盐”型阴离子药物递送剂包括几种酰氧基烷基-、烷基和芳基磷酸盐和膦酸盐二-和/或三-酯前药，它们是目前使用的或正在研究的治疗CNS相关疾病的AIDS和药物滥用治疗剂。随后，将研究这些试剂的完整体外水解评价。还将在Sprague道利大鼠中进行体内脑摄取研究，以评价增强所选磷酸盐/膦酸盐药物向CNS中递送的潜力。这些研究的结果预计将提供有价值的概念性信息的极性和电离药物的中枢神经系统/大脑的交付。(In鉴于工程计划的期限由五年改为三年，我们已减少了修订建议书内建议的化合物数目。具体变更摘要见具体目标部分。）

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.)