CNS TARGETED ANTIHIV AGENTS

中枢神经系统（CNS）的HIV感染可导致严重的 包括艾滋病相关的痴呆症。 然而，大脑排除了 许多有用的抗HIV药物由于血脑屏障 （BBB）。 这个项目试图提高大脑的渗透力 像F-ddA这样的化合物的特性，这一系列的原型药物， 和一种化合物，开始了一个国家癌症研究所赞助的抗艾滋病毒临床试验， 六月 正在探索的方法是设计和综合 具有改善的CNS转运性质的前药， 在穿过血脑屏障后转化为活性抗HIV药物。 的15 在本项目中合成的前药是 6-取代-2 '-氟二脱氧嘌呤核苷。 这些亲脂性 化合物可以被腺苷脱氨酶（ADA）转化为 2 '-β-氟二脱氧肌苷（F-ddI），一种已知具有抗HIV活性的化合物 活动 氟原子， f-ddI和临床上有用的药物ddI，增加了几个实用的 有益效果如酸稳定性，便于口服给药，和 减少酶催化剂。 我们最初的临床前研究表明 6-氯类似物可能具有最佳的 生产有效的CNS抗HIV剂所需的性质。 这 化合物与ddI相比已被给予大鼠。 药物 CSF和血浆水平，以及脑组织浓度， 被确定。

HIV infection of the central nervous system (CNS) can cause severe problems including AIDS-related dementia. However, the brain excludes many useful anti-HIV drugs as a consequence of the blood-brain-barrier (BBB). This project attempts to improve the brain penetration properties of compounds like F-ddA, the prototype drug in this series, and a compound which began an NCI-sponsored anti-HIV clinical trial in June. The approach being explored is the design and synthesis of prodrugs with improved CNS transport properties which are enzymatically converted to an active anti-HIV agent after crossing the BBB. The 15 prodrugs synthesized during this project are 6-substituted-2'-fluorodideoxypurine nucleosides. These lipophilic compounds can be converted by adenosine deaminase (ADA) to 2'-beta-fluorodideoxyinosine (F-ddI), a compound with known anti-HIV activity. The fluorine atom, the distinguishing difference between F-ddI and the clinically useful drug, ddI, adds several practical benefits such as acid-stability for ease of oral administration, and reduced enzymatic catabolism. Our initial preclinical studies indicate that the 6-chloro analog may possess the best combination of the properties required to produce an effective CNS anti-HIV agent. This compound has been administered to rats in a comparison with ddI. Drug CSF and plasma levels, as well as brain tissue concentrations, are being determined.