Design and Optimization of Novel Antimalarial Drugs

新型抗疟药物的设计与优化

• 批准号: 9248787
• 负责人: Michael Kevin RISCOE
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248787
• 关键词: 3-Dimensional; 4-aminoquinoline; Adverse effects; Africa South of the Sahara; Ames Assay; Amodiaquine; Antimalarials; Area; Artemisinins; Asia; Binding; Biological; Biological Availability; Cambodia; Cessation of life; Chemical Exposure; Child; Chloroquine; Chloroquine resistance; Clinical; Complex; Digit structure; Disclosure; Disease; Dose; Drug Kinetics; Drug toxicity; Exhibits; Fever; Health; Human; In Vitro; Infection; Lead; Legal patent; Libraries; Malaria; Manuscripts; Mediating; Medical; Medicine; Mefloquine; Metabolic; Methods; Modification; Multi-Drug Resistance; Mus; Neurologic; Oral; Parasites; Periodicity; Pharmaceutical Preparations; Pharmacotherapy; Plasmodium; Plasmodium falciparum; Positioning Attribute; Pregnant Women; Prevention; Property; Publishing; Quinine; Quinolones; Reaction Time; Readiness; Reporting; Research Activity; Resistance; Risk Assessment; Rodent; Rotation; Safety; Series; Side; Soldier; Stress; System; Testing; Therapeutic Intervention; Toxicant exposure; Veterans; Work; active method; analog; artesunate; clinically relevant; combat; design; drug standard; genotoxicity; global health; in vitro activity; in vivo; invention; killings; malaria infection; novel; novel therapeutics; prevent; public health relevance; quinoline; resistant strain; scaffold; screening; transmission process

 DESCRIPTION (provided by applicant) Objectives: To develop drugs for treatment and prevention of multidrug resistant malaria that are safe for use in children and pregnant women and that may be co-formulated with other drugs for prevention and treatment of active infections, for transmission blocking, and to aid in worldwide efforts to eradicate the disease. Introduction: For each of the estimated ≈1 million people killed each year by malaria there are hundreds that are severely sickened by the disease. 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 spread of Plasmodium strains that harbor resistance to multiple drugs including the quinolines chloroquine (CQ), amodiaquine (AQ), quinine and mefloquine. In some areas of the world, especially in SE Asia, multidrug resistance (MDR) has forced an absolute reliance on the artemisinin combined therapies for treatment of malaria. And now there are reports of increasing response times and artemisinin resistance in malaria parasites from Cambodia. Findings to date: We have used sontochin (SQ) as a guide to create "pharmachins" with alkyl or aryl substituents at the 3-position of the 4-aminoquinoline core. Modified with an aryl substituent PH-203 exhibits low nM IC50 values against MDR strains and in vivo efficacy against patent infections of P. yoelii in mice that is superior to CQ. With SQ and PH-203 as structural leads for optimization we have generated a library of >300 analogs varying the aryl substituent at the 3-position while optimizing the scaffol for in vitro activity and in vivo efficacy. Our results show that 3-position aryl pharmachins represent potential CQ and AQ replacement drugs. From here to there: We discovered that SQ is active against MDR P. falciparum strains. We then replaced the 3-position CH3 group with an aryl ring to produce analogs with impressive low nM IC50's vs. MDR strains, low ED50's vs. murine malaria, that were curative at 16 mg/kg in the 4-Day Peters test. Our efforts to optimize the 3-position aryl substituent as well as the 4-position side chain continue. For the proposed work we will focus on 3-position alkyl pharmachins, to optimize a sub-series with impressive antimalarial properties. Consider PH- 255with single digit nM IC50 values against MDR falciparum strains and with an ED50 value of less than 0.5 mg/kg against patent malaria infections in mice. Specific Aims: 1. To evaluate and optimize 3-position alkyl-pharmachins for antimalarial activity in vitro against MDR resistant strains of P. falciparum and in vivo vs. a rodent species of malaria, P. yoelii, 2. To evaluate and optimize 3-position alkyl-pharmachins for metabolic stability (t1/2) and fate in both murine and human microsomal systems and assessment of pharmacokinetics in vivo (in mice), 3. To conduct in vitro risk assessment tests on selected 3-position alkyl-pharmachins for potential genotoxicity in a prokaryotic system (Ames tests) and hERG channel inhibition, and 4. To establish the propensity for (and including mechanism of) 3-alkyl-pharmachin resistance in P. falciparum parasites (Dd2) in vitro. Methods: We will follow a standard drug optimization routine involving iterative synthesis and screening of 4- aminoquinoline analogs of the our lead 3-alkyl-pharmachins to enhance: in vitro potency against MDR P. falciparum parasites including clinical isolates from Cambodia with resistance to artemisinin; in vivo efficacy in malaria infected mice, metabolic stability, pharmacokinetics and safety. VA relevance: We seek to develop a safe CQ replacement drug for treating and preventing malaria without the neurological side effects of existing alternatives such as mefloquine. Rapid therapeutic intervention with a cocktail of safe antimalarial agents may avoid unnecessary toxic exposures (i.e., febrile conditions compounding the stress of warfare and combat readiness) that may otherwise have enduring long-term health consequences.

 描述(由申请人提供) 目的：开发治疗和预防多药耐药疟疾的药物，这些药物对儿童和孕妇使用是安全的，并且可以与其他药物共同配制，用于预防和治疗活动性感染，阻断传播，并帮助全球根除这种疾病的努力。导言：据估计，≈每年有100万人死于疟疾，每一人中就有数百人患有这种疾病。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，那里的受害者主要是幼儿和孕妇。由于对多种药物具有耐药性的疟原虫菌株的传播，情况正在恶化，这些药物包括喹啉类氯喹(CQ)、阿莫地喹(AQ)、奎宁和甲氟喹。在世界一些地区，特别是在东南亚，多药耐药迫使人们绝对依赖青蒿素联合疗法来治疗疟疾。现在有报道称，柬埔寨疟疾寄生虫的反应时间延长，对青蒿素产生抗药性。到目前为止的发现：我们已经使用sontoin(SQ)作为指南来创建在4-氨基喹啉核心的3-位具有烷基或芳基取代基的“药剂”。用芳基取代的PH-203修饰后，对多药耐药菌株显示出较低的NM IC50值，在小鼠体内对约氏P.yoelii的显性感染的效果优于CQ。以SQ和PH-203作为结构先导进行优化，我们已经建立了一个&gt；300类似物的文库，在优化支架的体外活性和体内疗效的同时，改变了3-位的芳基取代基。我们的结果表明，3位芳基药物是潜在的CQ和AQ替代药物。从这里到那里：我们发现SQ对恶性疟原虫多药耐药株具有活性。然后，我们用芳香环取代3-位CH3基团，生产出具有令人印象深刻的低NMIC50‘S与多药耐药株、低ED50’S与小鼠疟疾的类似物，在4天彼得斯试验中，这些类似物在16 mg/kg的剂量下即可治愈。我们继续努力优化3位芳基取代基和4位侧链。对于拟议的工作，我们将专注于3位烷基药物，以优化具有令人印象深刻的抗疟疾性能的子系列。以PH-255为例，其对耐多药恶性疟原虫株的NM IC50值为个位数，对小鼠的特发性疟疾感染的ED50值小于0.5 mg/kg。具体目的：1.评价和优化三位烷基药物在体外对耐多药恶性疟原虫株和体内对约氏疟原虫的抗疟疾活性；2.评估和优化三位烷基药物在小鼠和人微粒体系统中的代谢稳定性(T1/2)和去向，以及体内(在小鼠)的药代动力学；3.在原核系统(Ames试验)和HERG通道抑制系统中对选定的三位烷基药物进行潜在遗传毒性的体外风险评估试验。4.建立恶性疟原虫(DD2)对3-烷基耐药的倾向性(包括耐药机制)。方法：我们将遵循标准的药物优化程序，包括迭代合成和筛选我们的先导化合物3-烷基药物的4-氨基喹啉类似物，以提高：体外抗多药耐药恶性疟原虫的效力，包括柬埔寨临床分离株对青蒿素的抗药性；在疟疾感染小鼠的体内疗效、代谢稳定性、药代动力学和安全性。VA相关性：我们寻求开发一种安全的CQ替代药物，用于治疗和预防疟疾，而不会产生现有替代品(如甲氟喹)的神经副作用。使用安全的抗疟疾药物的鸡尾酒进行快速治疗干预，可以避免不必要的毒性暴露(即，发热条件加剧了战争和战备状态的压力)，否则可能会产生长期的健康后果。