Development of Novel Therapeutics for Leishmaniasis

项目摘要 本案无关利什曼原虫感染估计有1200万人，目前还没有令人满意的治疗方法。 但仍可用。该提案将推进3种支架，这些支架已经从表型筛选中出现， 开发针对利什曼病的新型有效口服生物可利用药物的先导物。摘要一 先前针对致病的利什曼原虫细胞内无鞭毛体阶段的表型筛选 已经确定了3种化学支架对无鞭毛体具有有效的功效。每一个被击中的化合物 对组织培养巨噬细胞中生长的无鞭毛体具有纳摩尔效力， 这些性质表明有希望开发一种新的口服生物可利用药物。每个支架的类似物将 制备并测试体外抗无鞭毛体的功效，最佳 吸收/分布/代谢/排泄/毒性（ADMET）特征，可接受的体内药代动力学 (PK)和在内脏利什曼病的鼠模型中控制疾病的功效。建立之后 初步的结构-活性关系，将进行广泛的药物化学计划， 开发具有最佳口服生物利用度药物总体特性的类似物， 在原版中出现的缺陷。每种支架对多种利什曼原虫的功效 和抗耐药田间分离株的能力将在早期阶段进行测试，以确定每种药物的潜力。 用于抗引起不同类型利什曼病的广泛寄生虫的适用性支架， 而对目前使用的其它抗利什曼病药物（尽管不是最佳的）没有预先建立的耐药性。的 将监测耐药性的发展速度，以确保所追踪的线索将得到合理的 在田间使用期间稳定防止抗性的出现。与一种广泛的药用 化学项目、体内药代动力学和急性毒性研究以及控制内脏感染的能力 将确定小鼠和仓鼠中来自原始3次命中的最高合成先导物。 总体目标是开发几种具有极有前途特性的潜在客户，以进行最终开发 迫切需要新的和有效的药物来对抗这种广泛的和控制不力的寄生虫 疾病

PROJECT SUMMARY Relevance. Leishmania parasites infect an estimated 12 million individuals, and no satisfactory treatments are yet available. This proposal will advance 3 scaffolds that have emerged from a phenotypic screen for development of leads towards novel effective orally-bioavailable drugs against leishmaniasis. Summary. A previous phenotypic screen against the disease-causing intracellular amastigote stage of Leishmania parasites has identified 3 chemical scaffolds with potent efficacy against amastigotes. Each hit compound exhibits nanomolar efficacy against amastigotes growing in tissue culture macrophages and has physical and chemical properties suggesting promise for development of a novel orally bioavailable drug. Analogs of each scaffold will be prepared and tested for efficacy against amastigotes in vitro, optimal absorption/distribution/metabolism/excretion/toxicity (ADMET) profiles, acceptable in vivo pharmacokinetics (PK), and efficacy in controlling disease in a murine model of visceral leishmaniasis. Following establishment of initial structure-activity relationships, an extensive medicinal chemistry program will be undertaken to develop analogs with the best overall properties for orally bioavailable drugs and to improve upon any potential deficits that emerge in the original hits. The efficacy of each scaffold against multiple species of Leishmania and against drug resistant field isolates will be tested at an early stage to ascertain the potential of each scaffold for applicability against a broad range of parasites causing distinct types of leishmaniasis and with or without pre-established resistance to other currently employed, albeit non-optimal, antileishmanial drugs. The rate of development of resistance will be monitored to ensure that leads that are pursued will be reasonably stable against emergence of resistance during use in the field. In association with an extensive medicinal chemistry program, in vivo pharmacokinetics and acute toxicity studies and ability to control visceral infections in mice and hamsters will be determined to arrive at the top synthetic leads originating from the original 3 hits. The overall objective is to develop several leads with highly promising characteristics for ultimate development of desperately needed novel and effective drugs against this widespread and poorly controlled parasitic disease.