PHOSPHOANIONIC DELIVERY OF ANTIAIDS & DRUG ABUSE ANTAGONISTS

相当数量的艾滋病患者和艾滋病-痴呆症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，艾滋病药物穿透血脑屏障、抑制HIV复制是缓解中枢神经系统功能障碍的关键。然而，在BBB，艾滋病药物如3‘-叠氮胸苷(AZT)、2’，3‘-二脱氧胞苷(DDC)的摄取率很低，因为这些药物的亲油性不足。即使当某些药物被看到穿透BB时，脑内的药物浓度也可能不足以阻止HIV的复制，一旦进入中枢/大脑，这些药物的半衰期也很低，因为它们具有极性和可电离的官能团。因此，我们推测，用亲脂性药物或亲脂性中枢神经系统药物通过‘磷酸’或‘膦酸’键化学掩蔽这些药物可能会产生一种磷酸盐/膦酸类阴离子递送剂(ADA)，由于其高亲脂性，它可以很容易地穿透BB，并在一段时间内缓慢地将具有生物活性的母体药物释放到中枢/大脑中。因此，拟议的研究旨在设计、合成和评估选定的艾滋病和药物滥用治疗药物的‘磷酸’和‘膦’型阴离子药物递送剂，以增强细胞递送、滞留和进入大脑/中枢神经系统的治疗效率，用于治疗艾滋病、艾滋病痴呆和药物滥用等脑部疾病。“磷酸”和“膦酸”类阴离子药物递送剂将包括几种酰氧基烷基、烷基和芳基磷酸盐和膦酸双酯和/或三酯类艾滋病前体药物，以及目前正在使用或正在研究中的药物滥用治疗药物，用于治疗中枢神经系统相关疾病。随后，将对这些制剂进行完整的体外水解性评价。体内脑摄取研究也将在SpragueDawley大鼠身上进行，以评估选定的磷酸盐/磷酸盐类药物增强向中枢神经系统输送的可能性。这些研究结果有望为将极性和电离药物输送到中枢神经系统/大脑提供有价值的概念性信息。(考虑到项目期限由5年改为3年，我们在这项修订建议中减少了建议化合物的数量。具体更改的摘要在特定目标一节中提供。)

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.)