CARBOVIR PRODRUGS--SYNTHESIS, METABOLISM, AND KINETICS

卡波韦是一种具有较强活性的新型碳环核苷。 在体外对抗冬虫夏草。该化合物已由 美国国立卫生研究院作为一种治疗艾滋病的有前途的药物。我们最近做了 建立了卡韦的高效液相色谱分析方法，并研究了 卡韦口服和静脉给药后的药代动力学 对老鼠的管理。卡韦启用时的生物利用度) 11.7±4.7%。目的：提高卡韦的口服吸收。我们建议 目的：合成和评价几类卡韦前药。 前药战略的第二个主要目标是增加 穿透到中枢神经系统。艾滋病患者有许多泌尿系疾病 可能直接由艾滋病毒脑部感染引起的问题。四 将合成几类前药：1)几种5‘-0H酯； 2)亲脂性卡韦单磷酸酯(卡韦-二磷酸- (L-双棕榈素)和双(酰氧甲基卡韦)酯- 磷酸：3A)6-氨基卡韦(腺苷脱氨酶 被激活)，3b)6-脱氧-卡韦(黄嘌呤氧化酶被激活4) 二氢吡啶/吡啶酯对中枢神经系统的选择性摄取。 系统的飞行员将做以下)实验：1)在 有血清、肝脏、脑或肠道酶的体外代谢 准备工作。2)所选药物的生物利用度的测定 前药与卡韦相比。3)中枢神经系统检查 卡韦及其前体药物。4)确定 前药的系统前代谢部位与肠道- 肝脏灌流模型系统。卡维韦的研究方法 前药也可以与其他有希望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.