OPTIMIZATION OF PRODRUGS FOR AZT/PFA RESISTANCE IN AIDS

描述(改编自摘要)：建议的是协作 两个研究小组之间的项目，一个由K.Y.Hostetler领导，另一个由 J.W.梅勒斯。它的主要目标是开发一种有用的前药 Foscarnet--或一种Foscarnet-AZT的“双亲药物”--用于艾滋病，它 口服的生物利用度是否有效，并能够克服对 Foscarnet和AZT。 具体目标是： (1)合成最佳烷基醚前体药磷甲酸钠和磷甲酸钠- AZT“双亲药物”，通过改变铅的结构参数 已经鉴定出的化合物。 (2)测定这些前体药物的体外活性和选择性 对抗野生型艾滋病毒和一系列耐药变体，包括 编码对膦甲酸钠、AZT和这两种药物耐药的基因。 (3)评估人类免疫缺陷病毒对前体药物耐药性的体外演变 Foscarnet和Foscarnet-AZT，从野生型和Foscarnet开始 和/或抗AZT物种。 (4)测定优化前体药的毒性和口服生物利用度。 小鼠体内抗野生型逆转录病毒活性的比较 小鼠SCID/Hu中对HIV、磷甲酸钠和/或AZT耐药的HIV株 模特。 这些目标的总体目标是开发一个有效的组合 AZT方案和磷甲酸甲酯的前体药物，或者，替代的，脂质前体- 用于治疗艾滋病的磷甲酸钠-氮卓酮类药物。

DESCRIPTION (adapted from the Abstract): Proposed is a collaborative project between two research groups, one led by K.Y. Hostetler and the by J.W. Mellors. It main objective is to develop a useful pro-drug of foscarnet--or a "double pro-drug" of foscarnet-AZT--for use in AIDS, which is bioavailable orally, effective, and able to overcome resistance to foscarnet and AZT. The specific aims are to: (1) Synthesize optimal alkyl ether pro-drugs of foscarnet and foscarnet- AZT "double pro-drugs," by varying structural parameters of the lead compounds already identified. (2) Determine the in vitro activity and selectivity of these pro-drugs against wild-type HIV and a panel of drug-resistant variants including those encoding resistance to foscarnet, AZT, and both drugs. (3) Assess the in vitro evolution of HIV resistance to pro-drugs of foscarnet and foscarnet-AZT, starting with both wild-type and foscarnet and/or AZT resistant species. (4) Determine toxicity and oral bioavailability of the optimized pro-drugs in mice and their comparative anti-retroviral activity against wild-type HIV and foscarnet and/or AZT resistant HIV strains in a murine SCID/HU model. The overall goal of these aims is to develop an effective combination of regimen of AZT and a pro-drug of foscarnet or, alternatively, a lipid pro- drug of foscarnet-AZT for therapy of AIDS.