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：开发治疗和预防耐多药疟疾的药物，这些药物可安全用于儿童和孕妇，并可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，并协助世界范围内根除该疾病的努力。导言：据估计，每年死于疟疾的人数为1000万，与此同时，也有数百人因疟疾而严重患病。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。由于疟原虫株的传播，这种情况正在恶化，疟原虫株对多种药物具有耐药性，包括喹啉类氯喹（CQ）、阿莫地喹（AQ）、奎宁和甲氟喹。在世界上的一些地区，特别是在东南亚，多药耐药性（MDR）迫使绝对依赖青蒿素联合疗法治疗疟疾。现在有报道说，柬埔寨的疟疾寄生虫的反应时间和青蒿素耐药性增加。迄今为止的调查结果：我们已经使用sontochin（SQ）作为指导来产生在4-氨基喹啉核心的3-位具有烷基或芳基取代基的“pharmachins”。用芳基取代基修饰的PH-203显示出对MDR菌株的低nM IC 50值，并且在小鼠中对约氏疟原虫的显性感染的体内功效优于CQ上级。使用SQ和PH-203作为优化的结构先导，我们已经产生了>300个类似物的文库，这些类似物在3-位上改变芳基取代基，同时优化了支架的体外活性和体内功效。我们的研究结果表明，3位芳基pharmachins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恶性疟原虫菌株有活性。然后，我们用芳基环取代3位CH 3基团以产生具有令人印象深刻的低nM IC 50对MDR菌株、低ED 50对鼠疟疾的类似物，其在4天Peters测试中在16 mg/kg下具有治愈性。我们继续努力优化3位芳基取代基以及4位侧链。对于所提出的工作，我们将专注于3-位烷基pharmachins，以优化具有令人印象深刻的抗疟特性的子系列。考虑PH-255，其对MDR恶性疟原虫株的IC 50值为个位数nM，对小鼠中的疟疾感染的ED 50值小于0.5 mg/kg。具体目标：1。为了评价和优化3-位烷基-pharmachins在体外针对恶性疟原虫的MDR抗性菌株和在体内相对于疟疾的啮齿动物物种约氏疟原虫的抗疟活性，2.为了评估和优化3-位烷基-pharmachins在鼠和人微粒体系统中的代谢稳定性（t1/2）和命运以及体内（小鼠中）药代动力学评估，3.对选定的3位烷基-pharmachins进行体外风险评估试验，以评估原核系统中的潜在遗传毒性（艾姆斯试验）和hERG通道抑制，以及4.确定体外恶性疟原虫（Dd 2）对3-烷基-pharmachin的耐药性倾向（包括耐药机制）。研究方法：我们将遵循标准药物优化程序，包括迭代合成和筛选我们的先导3-烷基-pharmachins的4-氨基喹啉类似物，以增强：针对MDR恶性疟原虫寄生虫的体外效力，包括来自柬埔寨的对青蒿素具有抗性的临床分离株;在疟疾感染小鼠中的体内功效、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，而不会产生甲氟喹等现有替代药物的神经副作用。用安全抗疟剂混合物进行快速治疗干预可以避免不必要的毒性暴露（即，发热状况加剧了战争和战备的压力），否则可能会对健康造成持久的长期影响。