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：开发用于治疗和预防多药抗性疟疾的药物，这些疟疾可安全用于儿童和孕妇，并且可以与其他药物共同形成，以预防和治疗主动感染，以进行传播阻塞，并帮助全球范围内的疾病努力。简介：每年估计有约100万人被疟疾杀死的人中有数百人因这种疾病而严重患病。的确，疟疾是当今世界上最常见的疾病和死亡原因之一，尤其是在撒哈拉以南非洲，受害者主要是幼儿和孕妇。由于疟原虫菌株的传播，这种情况令人担忧，这些疟原虫菌株具有抗多种药物的抗性，包括奎诺琳氯喹（CQ），氨二喹（aq），奎宁和甲氟喹。在世界某些地区，尤其是在SE亚洲，多药耐药性（MDR）迫使阿耳马赛蛋白合并疗法绝对缓解疟疾治疗。现在有报道称，柬埔寨疟疾人寄生虫的反应时间和青蒿素耐药性不断增加。迄今为止的发现：我们已经使用sontochin（sq）作为指南，以4-氨基氨基核心的3位位置与烷基或芳基亚识别创建“ Pharmachins”。用芳基亚tituent pH-203修饰的NM IC50值对MDR菌株和体内效率较低，而在小鼠中，对P. yoelii的专利感染则表现出低于CQ的小鼠的专利感染。以SQ和PH-203作为优化的结构引线，我们生成了一个> 300个类似物的库，在3位以3位的芳基体系变化，同时优化了体外活性和体内效率的支架。我们的结果表明，3位芳基药物代表潜在的CQ和AQ替代药物。从这里到那里：我们发现SQ对MDR P.恶性菌株具有活性。然后，我们用芳基环代替了3位CH3基团，以产生令人印象深刻的低NM IC50与MDR菌株，低ED50与鼠疟疾的类似物，在为期4天的彼得斯测试中，它们以16 mg/kg的速度治愈。我们为优化3位芳基亚定位以及4位侧链的努力继续。对于拟议的工作，我们将重点关注3位烷基药物，以优化具有令人印象深刻的抗疟疾特性的子系列。考虑对MDR恶性菌株的单位数字NM IC50值的pH-255，并且针对小鼠专利疟疾感染的ED50值小于0.5 mg/kg。 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 promise for (and including mechanism of) 3-alkyl-pharmachin resistance in P. falciparum parasites (Dd2) in vitro.方法：我们将遵循标准药物优化的常规，涉及迭代合成并筛选我们的铅3-烷基 - 帕尔玛丁的4-氨基喹啉类似物，以增强：针对MDR P. valciparum寄生虫的体外效力，包括来自cambodia的临床分离株，抗cambodia，抗cambodia均具有对小氨基氨基蛋白素的抗性；疟疾感染小鼠，代谢稳定性，药代动力学和安全性的体内效率。 VA相关性：我们试图开发一种安全的CQ替代药物来治疗和预防疟疾，而没有现有替代品（例如甲氟喹）的神经系统副作用。与安全抗疟疾药物的鸡尾酒快速治疗干预可能会避免不必要的有毒暴露（即，加剧了战争和战斗就绪压力的发热状况），否则可能会带来长期健康后果。