NEW BROAD SPECTRUM DRUGS FOR OPPORTUNISTIC INFECTIONS

这项研究的长期目标是开发新的、高活性的药物来治疗重要的艾滋病相关机会性病原体，包括肠道原生动物寄生虫小隐孢子虫和真菌病原体卡氏肺囊虫、白色念珠菌和新型隐球菌。SBIR I期研究已经确定了一种主要的候选药物2DPA 092，它在隐孢子虫病的新生小鼠模型中具有高度的口服活性，在卡氏疟原虫肺炎的大鼠模型中具有出色的静脉活性，与目前使用的药物喷他脒相比毒性降低，并且对白色念珠菌和新生念珠菌也有活性。目前没有临床证实有效的药物可用于治疗免疫功能低下个体的隐孢子虫病的毁灭性腹泻。因此，该研究的近期目标是获得足够的临床前数据，以申请FDA批准开始2DAP 092作为口服活性药物治疗隐孢子虫病的人体临床试验。该II期SBIR提案的具体目标是合成足够数量的2DAP 092，以进行正式的临床前毒性研究，以及进一步的药代动力学和ADME研究，以支持I期临床试验的IND申请。开发新的广谱药物，提高疗效，降低毒性，提高口服生物利用度，将是一个有价值的治疗艾滋病相关的机会性感染，占患者发病率和死亡率的大部分。特别需要开发任何具有隐孢子虫病临床活性的药物。

The long range goal of the research is to develop new, highly active drugs to treat important AIDS-associated opportunistic pathogens, including the intestinal protozoan parasite Cryptosporidium parvum and the fungal pathogens Pneumocystis carinii, Candida albicans and Cryptococcus neoformans. SBIR Phase I studies have identified a lead candidate drug, 2DPA 092, which is highly active orally in a neonatal mouse model of cryptosporidiosis, has excellent intravenous activity in a rat model of P. carinii pneumonia with reduce toxicity compared to the currently used drug pentamidine, and is also active against C. albicans and C. neoformans. No drugs with clinically proven efficacy are currently available to treat the devastating diarrhea of cryptosporidiosis in immunocompromised individuals. Therefore, the immediate goal of the research is to obtain sufficient preclinical data to apply for FDA approval to begin human clinical trials of 2DAP 092 as an orally active agent to treat cryptosporidiosis. The specific aims of this Phase II SBIR proposal are to synthesize sufficient quantities of 2DAP 092 to perform formal preclinical toxicity studies and further pharmacokinetic and ADME studies required to support to IND filing for Phase I clinical trials. PROPOSED COMMERCIAL APPLICATION The development of novel broad spectrum drugs, with improved efficacy, decreased toxicity and improved oral bioavailability, would be a valuable treatment for AIDS-related opportunistic infections, which account for the majority of the morbidity and mortality of patients. The development of any drug clinically active against Cryptosporidiosis is particularly needed.