PHOSPHONOFORMATE PRODRUGS AGAINST CNS RETROVIRUSES

抗中枢神经系统逆转录病毒的膦甲酸酯前药

• 批准号: 3139530
• 负责人: ANDRE ROSOWSKY
• 金额: $ 19.1万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-30 至 1991-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3139530
• 关键词: AIDS; AIDS therapy; Rauscher's virus; Retroviridae; Retroviridae disease; antiAIDS agent; antiviral agents; blood brain barrier; brain cell; brain disorder chemotherapy; carboxylate; chemical structure function; diacylglycerols; disease /disorder model; drug administration routes; drug design /synthesis /production; drug screening /evaluation; electron microscopy; formates; gestational age; histopathology; human immunodeficiency virus 1; hydropathy; ionic bond; laboratory mouse; mammalian embryology; membrane permeability; nervous system disorder chemotherapy; neurotropic virus; newborn animals; paralysis; pharmacokinetics; phosphonate; pregnancy circulation; prodrugs; radioimmunoassay; slow release drug; viral myelinopathy; virus antigen; virus infection mechanism; virus replication; zidovudine

The overall goal of this proposal is the synthesis of prodrug derivatives of known anti-retroviral agents with improved ability to cross the blood-brain barrier and the evaluation of these compounds for the ability to halt retroviral infection in a murine model designed to screen candidate anti-AIDS agents targeted against virally induced CNS disease. The antiviral agent to be used in phosphonoformic acid (PFA). Specific aims are: 1. To convert the very hydrophilic, negatively charged PFA molecule to lipophilic, less negative derivatives with favorable membrane diffusion properties and the ability to cross the blood- brain barrier. Depending on the latentiation group used, chemical and/or enzymatic release of PFA will occur at varying rates after entry into the CNS sanctuary. The proposed drugs will thus have the potential to act as sustained release formulations of PFA in the CNS. PFA will be modified at both the phosphonic and carboxylic acid moieties by ester and/or amide linkages. Pivaloyloxymethyl, dihydropyridyl, and diacylglyceride groups will be used to block PFA. 2. To perform biological evaluation of the PFA prodrugs in murine models that have been found useful in studies of the action of 3'-azido-3'-deoxythymidine (AZT) in the CNS. The test virus Cas-Br-E produces hind-limb paralysis in 3-5 months when injected inot newborn SWJ/R mice, and in 2-3 weeks when injected into midgestation embryos. Initially, virus replicates in the spleen and subsequently spreads to the CNS. Histopathology shows spongiform changes in gray matter of the spinal cord, cerebellum, and brain stem without inflammatory reaction. These pathological changes are similar to those seen in human AIDS patients with certain neurological syndromes. Work by the Co- Principal Investigator has recently shown that AZT, which is known to penetrate the blood-brain barrier, suppresses hind-limb paralysis and significantly prolongs life of Cas-Br-E infected mice in a dose-dependent manner. A rapid and cost-effective in vivo assay is thus already in place to perform side by side comparison of PFA and its lipophilic prodrug derivatives in a neurotropic virus model. The significance of this work lies in its potential to identify novel sustained release produrgs of PFA that will deliver the active agent to the CNS sanctuary for treatment of HIV infections of the CNS.

该提案的总体目标是综合前药 具有提高能力的已知抗逆转录病毒药物的衍生物 越过血脑屏障和评估 能够停止在鼠中停止逆转录病毒感染的能力的化合物 旨在筛选针对目标的候选抗AID剂的模型 针对病毒诱导的中枢神经系统疾病。 抗病毒剂为 用于磷酸化生物酸（PFA）。 具体目的是： 1。转换非常亲水的，带负电荷的PFA 分子到亲脂性，较少的负衍生物，有利 膜扩散特性以及越血的能力 脑屏障。 取决于所使用的延伸组，化学 PFA的酶释放和/或酶促释放将以不同的速度发生 进入中枢神经系统保护区。 因此，拟议的药物将具有 充当PFA持续释放公式的潜力 中枢神经系统。 PFA将在磷酸和 通过酯和/或酰胺连接的羧酸部分。 piveroyoyomy甲基，二氢吡啶基和二酰基甘油类化合物将 用于阻止PFA。 2。对PFA前药进行生物学评估 被发现在研究研究中有用的鼠模型 中枢神经系统中的3'-azido-3'-脱氧胸苷（AZT）。 测试病毒 CAS-BR-E在3-5个月内产生Hind-LIMB麻痹 注射新生儿SWJ/R小鼠，并在2-3周内 注射到中间胚胎中。 最初，病毒在 脾脏并随后扩散到中枢神经系统。 组织病理学 显示脊髓灰质的海绵变化， 小脑和脑干没有炎症反应。 这些 病理变化与在人类援助中看到的变化相似 患有某些神经系统综合征的患者。 共同工作 首席研究员最近表明，AZT是 已知可以穿透血脑屏障，可抑制后线 麻痹并显着延长CAS-BR-E感染小鼠的寿命 以剂量依赖的方式。 一个快速且具有成本效益的体内 因此，测定已经存在并排进行比较 PFA及其亲脂性前药衍生物在神经性病毒中 模型。 这项工作的意义在于它的潜力来识别新颖 PFA的持续释放产品将提供活跃 中枢神经系统保护区的特工治疗艾滋病毒感染 CNS。