AZIDE TECHNOLOGY FOR DRUG DEVELOPMENT

最近，佐治亚大学的朱夏莲教授， 埃默里大学的Raymond F.Schinazi教授和他的同事们 报道了6-叠氮嘌呤阿拉伯糖苷可被NADPH-还原。 细胞色素P450还原酶为阿糖腺苷(阿拉伯糖腺嘌呤， Ara-A或维达拉宾)。因此，叠氮嘌呤核苷可以起到 抗病毒活性药物的缓释剂与非常有利的血浆 半衰期、组织分布和药代动力学。基于他们的 有希望的初步结果和强大的专有地位， PharmAsset从埃默里大学和 佐治亚大学。我们计划探索这项技术，以改进 当前临床使用的某些药物的疗效，或使那些 具有良好的生物活性，但不能用于临床。 由于它们的代谢不稳定或溶解性问题，临床上 可用的代理。 在第一阶段，我们将合成三个新的6-叠氮嘌呤衍生物 临床使用的抗病毒药物阿昔洛韦、更昔洛韦和更昔洛韦的前药 喷昔洛韦和三个新的含叠氮基的核苷 阿糖胞苷、虫草素和阿糖胞苷前体药物的6位嘌呤环 克拉特里宾。Ara-G和虫草素显示出强大的抗肿瘤作用 活性，但Ara-G在水介质和虫草素中太不溶 会被脱氨基作用迅速灭活。克拉曲滨是一种临床药物， 但它需要静脉输液。这些药物的新叠氮前药 临床上重要的药物将被评估其抗癌和 抗病毒活性。与F.D.Boudinot教授合作 佐治亚大学的生物利用度和组织分布 将对新化合物进行研究。 在第二阶段，我们将选出一到两个最有希望的 化合物，并准备更大数量的临床前毒理学 以及申请IND所需的药理学研究 建议的商业应用： 有许多生物活性化合物，但它们的代谢 不稳定性或溶解性问题限制了它们的临床应用。我们的 技术将克服它们的一些限制，这将导致 以开发高度有用的临床药物。例如, 克拉曲滨，一种需要静脉输液的临床药物，将被 作为口服生物利用型前药开发。如果我们的第一阶段研究领先 对于药理有所改善的药物，它们的商业潜力将 要非常高。

Recently, Professor David C. K. Chu of the University of Georgia, Professor Raymond F. Schinazi of Emory University and colleagues reported that 6-azidopurine arabinoside can be reduced by NADPH- cytochrome P450 reductase to adenine arabinoside (arabinosyl adenine, ara-A or Vidarabine). As a result, the azidopurine nucleoside can act as a slow releaser of the active antiviral drug with very favorable plasma half-life, tissue distribution and pharmacokinetics. On the basis of their promising preliminary results and their strong proprietary position, Pharmasset licensed this technology from Emory University and the University of Georgia. We plan to explore this technology to improve efficacy of certain drugs currently used clinically, or to make those that have shown excellent biological activity, but could not be used in clinic due to their metabolic instability or solubility problems, clinically usable agents. In Phase I, we will synthesize three new 6-azidopurine derivatives as prodrugs of clinically used antiviral agents, Acyclovir, ganciclovir and penciclovir, and three novel nucleosides containing the azide group at the 6 position of the purine ring as prodrugs of ara-G, cordycepin and Cladribine. Ara-G and cordycepin have exhibited potent antineoplastic activity, but ara-G is too insoluble in aqueous medium and cordycepin is very rapidly inactivated by deamination. Cladribine is a clinical drug, but it requires intravenous infusion. The new azide prodrugs of these clinically important drugs will be evaluated for their anticancer and antiviral activities. In collaboration with Professor F. D. Boudinot of the University of Georgia, the bioavailability and tissue distribution of the new compounds will be studied. In Phase II, we will select one or two of the most promising compounds, and prepare larger amounts for preclinical toxicological and pharmacological studies required for an IND application PROPOSED COMMERCIAL APPLICATIONS: There are many biologically active compounds, but their metabolic instability or solubility problems limits their clinical use. Our technology would overcome some of their limitations, which will lead to the development of highly useful clinical drugs. For example, Cladribine, a clinical drug that requires intravenous infusion, will be developed as an orally bioavailable prodrug. If our Phase I studies lead to drugs with improved pharmacology, their commercial potential will be very high.