Benzoxaborole-based antimalarial drug discovery

修改后的项目摘要/摘要部分 迫切需要治疗疟疾的新药，最好是具有独特的化学结构和作用机制。最佳的抗疟药将是口服生物利用型的，具有更长的药理暴露时间，对儿童和孕妇服用是安全的，对红细胞疟疾寄生虫迅速有效，理想情况下也对其他生命周期阶段的疟疾寄生虫有效。这项申请建立在Anacor和UCSF最近的一项合作基础上，该合作将苯并氧硼化合物确立为有前途的新抗疟疾药物。最近，一项新的合作已经展开，包括加州大学旧金山分校的原始团队和现在Borgen的前Anacor合作者。我们推测，所提出的新型苯并恶环化合物将发挥强大的抗疟疾活性，并满足抗疟疾药物开发的必要标准。这项第一阶段的SBIR应用涉及研究新类别的苯并氧硼化合物，以便在第二阶段计划中为详细的发现和开发建立支架。我们的具体目标将是：1)表征苯并恶硼化合物抗疟疾活性的构效关系，2)表征具有抗疟疾活性的苯并恶硼化合物的类药物性质，3)表征根据目标1和目标2的研究结果选择的高级HITS的体内外活性、药物相互作用和初始药代动力学数据。我们预计，我们的研究将导致鉴定出多种具有良好体外活性(目标1)和良好的类药物特性(目标2)的化合物，为在目标3中进行更多的体外和体内研究奠定基础，然后在SBIR计划的第二阶段中更实质性地表征先导化合物。

Modified Project Summary/Abstract Section New drugs to treat malaria, ideally with unique chemical structures and mechanisms of action, are urgently needed. Optimal antimalarials will be orally bioavailable, have extended pharmacological exposure, be safe for administration to children and pregnant women, be rapidly active against erythrocytic malaria parasites, and ideally also be active against other life cycle stages of malaria parasites. This application builds on a recent collaboration between Anacor and UCSF that established benzoxaboroles as promising new antimalarial agents. Recently, a new collaboration has developed including the original team at UCSF and former Anacor collaborators now at Boragen. We hypothesize that the proposed novel benzoxaboroles will exert potent antimalarial activity and fulfill necessary criteria to enable progression to antimalarial drug development. This Phase I SBIR application concerns the study of new classes of benzoxaboroles to establish scaffolds for detailed discovery and development in a Phase II program. Our specific aims will be: 1) to characterize structure activity relationships for antimalarial activity of benzoxaboroles, 2) to characterize the drug-like properties of benzoxaboroles with antimalarial activity, and 3) to characterize ex vivo and in vivo activity, drug interactions, and initial pharmokinetic data for advanced hits selected based on results from Aim 1 and Aim 2 studies. We anticipate that our studies will lead to the identification of multiple compounds with promising in vitro activity (Aim 1) and favorable drug-like properties (Aim 2), laying the groundwork for advancement to additional in vitro and in vivo studies in Aim 3, and then to more substantial characterization of leads in Phase II of the SBIR program.