Aromatic Dication Prodrugs for CNS Trypanosomiasis

描述(申请人提供)：长期研究目标是开发一种治疗继发性(中枢神经系统)人类非洲锥虫病的新药。之前SBIR支持的研究确定了DB289，这是一种芳香族呋喃二甲胺的甲氧肟前体药物，目前正在进行LIB期临床试验，用于治疗早期非洲昏睡病。然而，DB289在中枢神经系统阶段锥虫病的动物模型中不能治愈。我们最近发现了新型氮杂类似物呋喃咪啶的烷基胺肟前药，对慢性小鼠感染模型有疗效。这一第一阶段SBIR应用的目标是合成足够数量的六种前体药物，以进行进一步的疗效、毒性和代谢研究。这些具体目标旨在允许在第二阶段研究期间选择一种主要候选化合物加入到中枢神经系统感染的灵长类动物模型的高级疗效测试中，并进入正式的临床前毒性测试。这项研究可能会导致开发一种有效、安全和经济的新药来治疗这种毁灭性的原虫寄生虫感染，目前估计在非洲最近爆发的疫情中，这种寄生虫感染导致30多万人死亡。

DESCRIPTION (provided by applicant): The long-range research goal is to develop a new drug to treat secondary (central nervous system) stage human African trypanosomiasis. Previous SBIR supported research identified DB289, a methoxime prodrug of the aromatic dication furamidine, that is currently progressing in Phase lib clinical trials for treatment of early stage African sleeping sickness. DB289, however, is not curative in animal models of CNS stage trypanosomiasis. We have recently identified alkylamidoxime prodrugs of novel aza analogs of furamidine that are curative in a chronic mouse model of infection. The objective of this Phase I SBIR application is to synthesize sufficient quantities of six prodrugs to perform further efficacy, toxicity and metabolism studies. The specific aims are designed to permit selection of a lead candidate compound to enroll during Phase II research into advanced efficacy testing in a primate model of CNS infection and into formal preclinical toxicity testing. The research may lead to development of a potent, safe and economical new drug to treat this devastating protozoan parasitic infection currently estimated to be killing over 300,000 people in recent outbreaks in Africa.