Boron-containing antimalarial drug discovery

项目总结 治疗疟疾的新药迫在眉睫，最好是具有独特的化学结构和作用机制 需要的。治疗和预防疟疾的最佳候选药物将具有强大的抗击疟疾活性 在培养的寄生虫和疟疾的动物模型中，对红细胞疟疾寄生虫迅速有效， 口服生物利用度，有较长的药理暴露，对人类是安全的。这 应用建立在我们小组先前的研究基础上，该研究确定苯并氧硼环类化合物是有希望的抗疟疾药物和 反应生物科学公司和加州大学旧金山分校之间的第一阶段SBIR项目，确定了两个新的系列硼- 含有有效抗疟疾活性的化合物。此程序的第二阶段将允许我们执行 彻底的领先优化计划，旨在提供有效的候选抗疟疾化合物， 口服生物利用度，使用安全。因此，我们的具体目标将是：1)优化抗疟疾 含铅含硼化合物的活性和类药物性质，2)作用机理表征 和抗药性驱动铅优化，3)表征药代动力学曲线，体内抗疟疾 优化的含硼抗疟药的有效性和安全性，以及4)改进了优化的含硼抗疟药 复合到候选人状态。

PROJECT SUMMARY New drugs to treat malaria, ideally with unique chemical structures and mechanisms of action, are urgently needed. Optimal drug candidates for the treatment and prevention of malaria will have potent activity against cultured parasites and in animal models of malaria, be rapidly active against erythrocytic malaria parasites, be orally bioavailable, have extended pharmacological exposure, and be safe for administration to humans. This application builds on prior studies by our group that identified benzoxaboroles as promising antimalarials and a Phase I SBIR project between Reactive Biosciences and UCSF that identified two new series of boron- containing compounds with potent antimalarial activity. Phase II of this program will allow us to execute a thorough lead optimization program designed to deliver a candidate antimalarial compound that is potent, orally bioavailable, and safe for use. Accordingly, our specific aims will be to: 1) optimize the antimalarial activity and drug-like properties of lead boron-containing compounds, 2) characterize mechanisms of action and resistance to drive lead optimization, 3) characterize the pharmacokinetic profiles, in vivo antimalarial efficacy, and safety of optimized boron-containing antimalarials, and 4) advance an optimized boron-containing compound to Candidate status.