Design and Optimization of Novel Antimalarial Drugs

新型抗疟药物的设计与优化

• 批准号: 9898269
• 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/9898269
• 关键词: 3-Dimensional; 4-aminoquinoline; 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; Structure; 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; malaria infection; novel; novel therapeutics; prevent; public health relevance; quinoline; resistant strain; scaffold; screening; side effect; 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） 目标：开发用于治疗和预防多重耐药性疟疾的药物，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，并协助全世界根除该疾病的努力。简介：据估计，每年约有 100 万人死于疟疾，其中每人就有数百人因该疾病而病情严重。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（包括喹啉氯喹（CQ）、阿莫地喹（AQ）、奎宁和甲氟喹）具有抗药性的疟原虫菌株的传播，情况正在恶化。在世界某些地区，特别是在东南亚，多重耐药性（MDR）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和青蒿素耐药性不断增加。迄今为止的发现：我们以sontochin (SQ)为指导，创建了在4-氨基喹啉核心的3位上带有烷基或芳基取代基的“pharmachins”。用芳基取代基修饰的 PH-203 对 MDR 菌株表现出较低的 nM IC50 值，并且对小鼠约氏疟原虫明显感染的体内功效优于 CQ。以 SQ 和 PH-203 作为优化的结构先导，我们生成了超过 300 个类似物的库，改变了 3 位芳基取代基，同时优化了支架的体外活性和体内功效。我们的结果表明，3 位芳基 pharmachin 代表了潜在的 CQ 和 AQ 替代药物。从这里到那里：我们发现 SQ 对 MDR 恶性疟原​​虫菌株具有活性。然后，我们将 3 位 CH3 基团替换为芳基环，以产生与 MDR 菌株相比具有令人印象深刻的低 nM IC50、与鼠疟疾相比低 ED50 的类似物，这些类似物在 4 天 Peters 测试中在 16 mg/kg 时具有疗效。我们仍在继续努力优化 3 位芳基取代基和 4 位侧链。对于拟议的工作，我们将重点关注 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，其针对 MDR 恶性疟原​​虫株的 IC50 值为个位数，针对小鼠明显疟疾感染的 ED50 值小于 0.5 mg/kg。具体目标： 1. 评估和优化 3-位烷基-pharmachins 在体外对抗 MDR 耐药菌株的抗疟活性。 2. 评估和优化 3-位烷基-pharmachins 在小鼠和人类微粒体系统中的代谢稳定性 (t1/2) 和命运并进行评估 体内药代动力学（小鼠），3. 对选定的 3-位烷基-pharmachins 在原核系统中的潜在遗传毒性（Ames 测试）和 hERG 通道抑制进行体外风险评估测试，以及 4. 建立恶性疟原虫（Dd2）体外对 3-烷基-pharmachin 耐药的倾向（包括机制）。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领先的 3-烷基药物的 4-氨基喹啉类似物，以增强： 体外对抗 MDR 恶性疟原​​虫的效力，包括来自柬埔寨的对青蒿素耐药的临床分离株；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，且不会产生甲氟喹等现有替代药物的神经副作用。使用安全抗疟药物混合物进行快速治疗干预可以避免不必要的有毒物质暴露（即加剧战争和战备压力的发热情况），否则可能会产生持久的长期健康后果。