CARBOVIR PRODRUGS--SYNTHESIS, METABOLISM, AND KINETICS

卡波韦是一种新的碳环核苷类药物， 在体外对抗HIY。 该化合物已被选定的 NIH for Development作为一种有前途的艾滋病药物。 我们最近 开发了一种高效液相色谱法测定卡波韦，并研究了 口服和静脉注射后卡波韦的药代动力学 给大鼠施用。 如果使用卡波韦， 11.7 ± 4.7%。提高卡波韦的口服吸收。我们提出 合成并评价几类卡波韦前体药物。 前药策略的第二个主要目标是增加 渗透到CNS。 艾滋病患者有许多泌尿系统疾病， 这些问题可能直接归因于HIV脑部感染。 四 将合成以下类别的前药：1）几种5 ′-OH酯; 2)亲脂性卡波韦单磷酸酯（卡波韦-二磷酸酯- L-二棕榈精）和卡布韦的双（酰氧基甲基）酯。 单磷酸盐：3a.）腺苷脱氨酶 激活），3b.）6-脱氧-卡波韦（黄嘌呤氧化酶活化4） 用于选择性CNS摄取的二氢吡啶/吡啶鎓酯。 系统的飞行员将进行以下实验：1）在 血清、肝、脑或肠酶的体外代谢 准备工作2)测定所选药物的生物利用度 前药与卡波韦比较动物。3)CNS检查 如果卡波韦及其前体药物具有渗透性。4)测定 前体药物的全身前代谢位点与肠- 肝脏灌注模型系统。 开发的Carbovir方法 前药也可与其它有前途的抗病毒药物一起使用 核苷

Carbovir is a new carbocyclic nucleoside that has potent activity against the HIY in vitro. The compound has been selected by the NIH for Development as a promising drug for AIDS. We have recently developed an HPLC assay For carbovir and have studied the pharmacokinetics of carbovir after oral and intravenous administrations to rats. The bioavaibility if carbovir was on)y 11.7+4.7%. To improve the oral absorption of carbovir. we propose to synthesize and evaluate several classes of carbovir prodrugs. A second major goal of a prodrug strategy is to increase penetration into the CNS. AIDS patients have many reurologicai problems that may be directly due to an HIV brain infection. Four classes of prodrugs will be synthesized: 1) Several 5'-0H esters; 2) Lipophilic carbovir monophosphate esters (carbovir-diphosphate- L-dipalmitin) and bis(acyloxymethyl) esters of carbovir- morphosphate: 3a.) 6-amino-carbovir (adenosine deaminase activated), 3b.) 6-deoxy-carbovir(xanthine oxidase activated 4) Dihydropyridine/ pyridinium esters for selective CNS uptake. Systematic aviator will be done to the follow) experiments: 1) In vitro metabolism with serum, liver, brain, or intestinal enzyme preparations. 2) Determination of the bioavaibility of selected Prodrugs compared to carbovir tn animals. 3) Examination of CNS peretratical if carbovir and its prodrugs. 4) Determination of the site of pre-systemic metabolism of the prodrugs with an intestinal- liver perfusion model system. The methods developed for carbovir prodrugs may also be used with other promising antiviral nucleosides.