Development of a Chloroquine Replacement Drug

氯喹替代药物的开发

• 批准号: 7937021
• 负责人: Michael Kevin RISCOE
• 金额: $ 46.95万
• 依托单位: PORTLAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937021
• 关键词: Address; Africa South of the Sahara; Antimalarials; Antiparasitic Agents; Area; Asia; Biogenic Amines; Cessation of life; Chemicals; Child; Chloroguanide; Chloroquine; Chloroquine resistance; Development; Disease; Drug Formulations; Exhibits; Fansidar; Folic Acid Antagonists; Human; In Vitro; Inhibitory Concentration 50; Lead; Malaria; Mefloquine; Metabolic; Molecular Weight; Multi-Drug Resistance; Mus; Oral; Parasites; Pharmaceutical Preparations; Pharmacology; Phenotype; Plasmodium; Plasmodium falciparum; Pregnant Women; Publishing; Pyrimethamine-Sulfadoxine; Quinine; Reaction; Reliance; Reporting; Research Design; Resistance; Rodent; Safety; Science; Sodium Chloride; System; Testing; Therapeutic; Translations; Tropical Disease; Vulnerable Populations; Work; artesunate; atovaquone; chemotherapeutic agent; combat; complement C2b; cost; genotoxicity; in vitro activity; in vitro testing; in vivo; killings; malarone; neglect; preclinical study; public health relevance; quinoline; receptor; resistant strain; respiratory

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.

描述（由申请人提供）：本申请涉及广泛的挑战领域 (15) 翻译科学和具体挑战主题，15-AI-103* 开发治疗被忽视的热带疾病的药物，特别强调疟疾。就每年的死亡人数而言，疟疾仍然是当今世界上最致命的疾病之一，几千年来一直如此。每年有 100 万人死亡，其中有数百人因疟原虫而病情严重。事实上，疟疾是当今世界最常见的疾病和死亡原因之一，尤其是在撒哈拉以南非洲地区，其受害者主要是幼儿和孕妇。由于对多种药物具有抗药性的疟原虫菌株的出现和传播，情况正在恶化，这些药物包括：喹啉类药物——氯喹、奎宁和甲氟喹；抗叶酸剂 - 乙胺嘧啶和磺胺多辛；以及阿托伐醌和氯胍的抗呼吸系统组合。在世界某些地区，特别是在东南亚，多重耐药性迫使人们绝对依赖内过氧化物青蒿琥酯来治疗疟疾——疟疾治疗选择彻底崩溃的阻力之墙如剃刀般薄弱。我们发现了一类化合物，我们称之为“Pharmachins”，对恶性疟原虫的多重耐药菌株具有同等和有效的活性，包括对氯喹、奎宁、甲氟喹、范西达和马拉隆具有高水平耐药性的菌株。我们目前的先导分子 Pharmachin 128 (PH128) 对所有测试菌株（例如 D6、Dd2、7G8 和 Tm90-C2B）均表现出低纳摩尔范围内的 IC50 值。 PH128 通过口服方式在伯氏疟原虫和约氏疟原虫感染的小鼠中具有活性，在改良的 4 天测试中，ED50 值为约 2.7 毫克/千克/天，ED90 值为约 4.6 毫克/千克/天（即，药物管理从证明通畅开始）。这些值与已发表的氯喹在这两个系统中的作用概况报告惊人地相似。我们认为 PH128 是替代氯喹的优秀先导候选药物。 PH128 具有被认为是新型抗疟药非常理想的物理、化学和药理学品质 - 易于合成、低成本、非手性、低分子量（例如 < 500）、log P 值 < 5、稳定的盐配方，以及在体外和体内均具有很强的抗寄生虫作用，甚至针对多重耐药菌株。在拟议的工作中，我们寻求显着加速 Pharmachin 发现的转变，通过一系列具有挑战性的临床前研究来推进两种非常强大的先导候选药物，这些临床前研究旨在优化抗寄生虫活性、功效、代谢稳定性、安全性和递送。下面概述了这些研究，并在叙述中提供了更多细节。具体目标： 1. 优化 Pharmachins 对恶性疟原虫多重耐药菌株的体外抗疟活性，以及​​对两种不同疟原虫 P. yoelii 和 P. berghei 的体内抗疟活性，2. 评估 Pharmachins 的代谢稳定性（ t1/2) 以及小鼠和人类微粒体系统中 CYP450 反应表型的命运以及体内药理学评估， 3. 评估选定的 Pharmachins 在原核系统中的潜在遗传毒性， 4. 进行体外测试以评估 Pharmachins 与生物胺转运蛋白/受体的特异性相互作用以及 hERG 通道抑制作用， 5. 对 PH128（以及另一种药物）进行毒理学评估主要候选者）在小鼠中，以及 6. 确定恶性疟原虫寄生虫（Dd2）对 Pharmachin 128 耐药的倾向体外。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多重耐药性疟疾，甚至在最脆弱的人群、孕妇和幼儿中也是如此。此外，Pharmachins 代表了该实验室总体承诺的重要组成部分，即开发可用于根除疟疾的化疗药物混合物。 公共健康相关性：本申请涉及广泛的挑战领域 (15) 转化科学和具体挑战主题，15-AI-103* 开发治疗被忽视的热带疾病的药物，特别是疟疾。