Development of a Chloroquine Replacement Drug

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）翻译科学和具体的挑战主题，15-AI-103* 开发被忽视的热带疾病的药物，特别强调疟疾。关于每年死亡人数，疟疾仍然是当今世界最致命的疾病之一，几千年来一直如此。每年有100万人死于疟疾，其中有数百人因疟疾寄生虫而严重患病。事实上，疟疾是当今世界最常见的疾病和死亡原因之一，特别是在撒哈拉以南非洲，那里的受害者主要是幼儿和孕妇。由于疟原虫寄生虫株的出现和传播，情况正在恶化，这些疟原虫寄生虫株对多种药物具有耐药性，包括：喹啉类-氯喹，奎宁和甲氟喹;抗叶酸剂-乙胺嘧啶和磺胺嘧啶;以及阿托伐醌和氯胍的抗呼吸组合。在世界上的一些地区，特别是在东南亚，多药耐药性迫使绝对依赖内过氧化物青蒿琥酯治疗疟疾-这是一堵反对疟疾治疗选择全面崩溃的薄薄的墙。我们已经发现了一类我们称为“Pharmachins”的化合物，其对恶性疟原虫的多药抗性菌株具有同等和有效的活性，所述恶性疟原虫的多药抗性菌株包括对氯喹、奎宁、甲氟喹、Fansidar和Malarone具有高水平抗性的菌株。我们目前的先导分子Pharmachin 128（PH 128）对所有测试菌株的IC 50值均在低纳摩尔范围内，例如，D 6、Dd 2、7 G8和Tm 90-C2B。在伯氏疟原虫和约氏疟原虫感染的小鼠中，通过口服方式施用PH 128是有活性的，在改良的4天试验中ED 50值为约2.7mg/kg/天，ED 90值为约4.6mg/kg/天（即，药物给药开始于显示开放性）。这些数值与已发表的氯喹在这两个系统中的作用特征报告惊人地相似。我们认为PH 128是替代氯喹的优秀候选药物。PH 128表现出在新的抗疟药中被认为是高度期望的物理、化学和药理学性质-易于合成、商品成本低、非手性、低分子量（例如，< 500），log P值< 5，稳定的盐制剂，以及强的体外和体内抗寄生虫作用，甚至针对多药耐药菌株。在拟议的工作中，我们寻求通过一系列具有挑战性的临床前研究来大幅加速我们的Pharmachin发现的过渡，以推进两个非常强大的领先候选人，这些研究旨在优化抗寄生虫活性，疗效，代谢稳定性，安全性和交付。这些研究大致概述如下，叙述中提供了更多细节。具体目标：1。为了优化Pharmachins在体外针对恶性疟原虫的多药耐药菌株以及在体内针对两种不同的疟疾啮齿动物物种约氏疟原虫和伯氏疟原虫的抗疟活性，2.评价Pharmachins在鼠和人微粒体系统中的代谢稳定性（t1/2）和CYP 450反应表型的结局以及体内药理学评估，3.评价选定Pharmachins在原核系统中的潜在遗传毒性，4.进行体外试验以评估Pharmachins与生物胺转运蛋白/受体的特异性相互作用以及hERG通道抑制，5.在小鼠中进行PH 128（和另一种先导候选物）的毒理学评估，以及6.确定体外恶性疟原虫（Dd 2）对Pharmachin 128的耐药性倾向。总之，我们假设Pharmachins可以作为负担得起的“氯喹替代药物”，可以在全球范围内用于对抗耐多药疟疾，即使是在最脆弱的人群，孕妇和幼儿中。此外，Pharmachins代表了该实验室开发可用于根除疟疾的化疗药物鸡尾酒的整体承诺的重要组成部分。 公共卫生相关性：此应用程序解决了广泛的挑战领域（15）翻译科学和特定的挑战主题，15-AI-103* 开发被忽视的热带疾病的药物，特别强调疟疾。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translation Science and Specific Challenge Topic, 15-AI-103* Develop drugs for neglected tropical diseases, with a special emphasis on malaria. With regard to the annual toll of people killed, malaria remains one of the deadliest diseases in the world today, as it has been so for thousands of years. For each of the 1 million people killed each year there are hundreds that are severely sickened by malaria parasites. Indeed, malaria is one of the most frequent causes of sickness and death in the world today but especially in sub-Saharan Africa where its victims are primarily young children and pregnant women. And the situation is worsening due to the emergence and spread of strains of Plasmodium parasites that harbor resistance to multiple drugs including: the quinolines - chloroquine, quinine, and mefloquine; the antifolates - pyrimethamine and sulfadoxine; and the anti-respiratory combination of atovaquone and proguanil. In some areas of the world, especially in SE Asia, multidrug resistance has forced an absolute reliance on the endoperoxide artesunate for treatment of malaria - a razor thin wall of opposition to a total collapse of therapeutic options for malaria. We have discovered a class of compounds which we refer to as "Pharmachins" with equal and potent activity against multidrug resistant strains of Plasmodium falciparum including strains harboring high level resistance to chloroquine, quinine, mefloquine, Fansidar and Malarone. Our current lead molecule, Pharmachin 128 (PH128), exhibits IC50 values in the low nanomolar range against all tested strains, e.g., D6, Dd2, 7G8 and Tm90-C2B. PH128 is active by oral means of administration in P. berghei and P. yoelii-infected mice with ED50 values of ~2.7mg/kg/day and ED90 values of ~4.6mg/kg/day in modified 4-day tests (i.e., drug administration begins with demonstration of patency). These values are strikingly similar to published reports of chloroquine's action profile in these two systems. We feel that PH128 represents an excellent lead candidate to replace chloroquine. PH128 exhibits physical, chemical and pharmacological qualities that are considered highly desirable in a new antimalarial - ease of synthesis, low cost of goods, achiral, low molecular weight (e.g., < 500), log P value < 5, stable salt formulation, and strong antiparasitic action in vitro and in vivo, even against multidrug resistant strains. In the proposed work we seek to dramatically accelerate the transition of our Pharmachin discoveries to advance two very strong lead candidates through a challenging array of preclinical studies designed to optimize antiparasitic activity, efficacy, metabolic stability, safety, and delivery. These studies are broadly outlined below with greater detail provided in the narrative. Specific Aims: 1. To optimize Pharmachins for antimalarial activity in vitro against multidrug resistant strains of P. falciparum and in vivo vs. two different rodent species of malaria, P. yoelii and P. berghei, 2. To evaluate Pharmachins for metabolic stability (t1/2) and fate with CYP450 reaction phenotyping in both murine and human microsomal systems and assessment of pharmacology in vivo, 3. To evaluate selected Pharmachins for potential genotoxicity in a prokaryotic system, 4. To conduct in vitro tests to assess Pharmachins for specific interactions with biogenic amine transporters/receptors and for hERG channel inhibition, 5. To conduct toxicological assessment of PH128 (and another lead candidate) in mice, and 6. To establish the propensity for Pharmachin 128 resistance in P. falciparum parasites (Dd2) in vitro. In summary, we hypothesize that Pharmachins can serve as affordable "chloroquine replacement drugs" that can be used on a worldwide scale to combat multidrug resistant malaria even in the most vulnerable populations, pregnant women and young children. Furthermore, Pharmachins represent an important component of this lab's overall commitment to developing a cocktail of chemotherapeutic agents that can be used to eradicate malaria. PUBLIC HEALTH RELEVANCE: This application addresses broad Challenge Area (15) Translation Science and Specific Challenge Topic, 15-AI-103* Develop drugs for neglected tropical diseases, with a special emphasis on malaria.