NOVEL HIV1 SPECIFIC NON-NUCLEOSIDE RT INHIBITOR

这项建议是开发一种HIV-1特异性非核苷类RT 抑制剂。该化合物已被证明具有EC50值 对实验室和临床艾滋病毒的检测范围为0.4-1.7微米- 分离株在体外XTT试验中。它还能有效地对抗艾滋病毒。 Y181C突变株对抗3TC耐药株 M184I的RT突变及其对HEPT耐药株的作用 P236L基因突变。此外，该化合物还显示出有效的 EC50值相当的抗人巨细胞病毒活性 比更昔洛韦更昔洛韦好。进一步的药理学和毒理学 该药物的评估将是这一阶段SBIR的重点 程序，其中包括合成一公斤的(+)-12- 氧卡拉内酯A，改进(+)-12-的合成工艺 氧卡拉内酯A，并进行急性单剂量毒性研究。 毒性研究将检查口服和静脉给药的情况 两种哺乳动物中的抑制物，并开始初步 药代动力学实验。该SBIR计划的最终目标是 将在年底向FDA提交IND申请 第二阶段SBIR，并启动一项I/II阶段临床试验。

This proposal is to develop a HIV-1 specific nonnucleoside RT inhibitor. This compound has been shown to have EC50 values ranging from 0.4-1.7 microM against both laboratory and clinical HIV- isolates in the in vitro XTT assay. It is also active against HIV isolates with a mutation of Y181C, against 3TC-resistant isolates with an RT mutation of M184I, and against HEPT-resistant isolates with a mutation of P236L. Furthermore, the compound exhibits potent activity against human cytomegalovirus with an EC50 value comparable to that of ganciclovir. Further pharmacological and toxicological evaluations of the drug will be the focus of this phase I SBIR program, which include synthesis of one kilogram of (+)-12- oxocalanolide A, improving the synthetic processes of (+)-12- oxocalanolide A, and performing the acute single-dose toxicity studies. The toxicity study will examine oral and intravenous administration of the inhibitor in two mammalian species, and begin preliminary pharmacokinetic experiments. The ultimate goal for this SBIR program will be to file an IND application with the FDA at the end of the Phase II SBIR and to initiate a Phase I/II clinical trial.