AZIDE TECHNOLOGY FOR DRUG DEVELOPMENT

用于药物开发的叠氮化物技术

• 批准号: 6403446
• 负责人: KYOICHI A WATANABE
• 金额: $ 13.29万
• 依托单位: PHARMASSET, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-15 至 2003-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6403446
• 关键词: amination; antineoplastics; antiviral agents; azides; chemical synthesis; deoxyadenosines; drug design /synthesis /production; laboratory mouse; laboratory rat; pharmacokinetics; prodrugs

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.

最近，大卫·C.教授K.格鲁吉亚大学的朱， Raymond F.埃默里大学的Schinazi及其同事 报道6-叠氮嘌呤阿拉伯糖苷可以被NADPH还原- 细胞色素P450还原酶转化为腺嘌呤阿拉伯糖苷（阿拉伯糖基腺嘌呤， ara-A或阿糖腺苷）。因此，叠氮嘌呤核苷可以作为 一种活性抗病毒药物的缓慢释放剂， 半衰期、组织分布和药代动力学。根据其 有希望的初步结果和他们强大的专有地位， Pharmasset从埃默里大学和 格鲁吉亚大学。我们计划探索这项技术， 目前临床上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性或溶解性问题， 可用的代理人。 在第一阶段，我们将合成三种新的6-叠氮嘌呤衍生物， 临床上使用的抗病毒剂的前药，阿昔洛韦，更昔洛韦和 阿昔洛韦和三个新的核苷含有叠氮基， 嘌呤环的6位作为ara-G、虫草素和 克拉屈滨阿糖胞苷和虫草素表现出了很强的抗肿瘤作用， 活性，但ara-G太不溶于水介质和虫草素 通过脱氨基作用非常迅速地失活。克拉屈滨是一种临床药物 但需要静脉注射这些化合物的新的叠氮化物前药 临床上重要的药物将被评估其抗癌和 抗病毒活性。与F教授合作。D.布迪诺 格鲁吉亚大学，生物利用度和组织分布 将研究新化合物。 在第二阶段，我们将选择一个或两个最有前途的 化合物，并制备更大量的临床前毒理学 IND申请所需的药理学研究 拟议的商业应用： 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 技术将克服他们的一些局限性，这将导致 发展出非常有用的临床药物。比如说， 克拉屈滨是一种需要静脉输注的临床药物， 开发为口服生物可利用的前药。如果我们的第一阶段研究 到药理学得到改善的药物，它们的商业潜力将 非常高。