Pharmachin Optimization and Testing

Pharmachin 优化和测试

• 批准号: 10260927
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10260927
• 关键词: 4-aminoquinoline; Africa South of the Sahara; American soldier; Amodiaquine; Antimalarials; Artemisinins; Attention; Award; Binding; Biological; Blood; Budgets; Cardiac; Cardiotoxicity; Cessation of life; Chemical Exposure; Chemoprevention; Child; Chloroquine; Chloroquine resistance; Clinical; Complex; Cresol; Development; Disease; Drug Kinetics; Drug toxicity; Exhibits; Fever; Future; G6PD gene; Goals; Health; Hemolytic Anemia; Human; In Vitro; Individual; Infection; Knowledge; Lead; Learning; Legal patent; Malaria; Mammalian Cell; Mannich Bases; Mediating; Medical; Mefloquine; Metabolic; Modeling; Modification; Multi-Drug Resistance; Mus; Neurologic; Oral; Parasites; Pharmaceutical Preparations; Plasmodium falciparum; Plasmodium vivax; Positioning Attribute; Preclinical Testing; Pregnant Women; Prodrugs; Prophylactic treatment; Publishing; Quinine; Recording of previous events; Reporting; Resistance; Risk; Risk Assessment; Rodent; Rotation; Route; Safety; Series; Side; Strategic Planning; Stress; Structure; System; Testing; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Toxicant exposure; Veterans; Vivax Malaria; Vulnerable Populations; Work; artesunate; clinically relevant; combat readiness; combat veteran; cytotoxicity; design; drug metabolism; efficacy trial; experience; global health; improved; in vitro activity; in vivo; lead candidate; member; morpholine; mouse model; novel; novel therapeutics; pre-clinical; preclinical development; prevent; quinoline; resistant strain; scaffold; side effect; success; transmission process; warfighter

We seek to develop a potent Pharmachin derivative with activity against blood forms of P. falciparum and P. vivax. It is our ultimate goal to develop an inexpensive anti-malarial that is safe for use in G6PD deficient individuals, and in the most vulnerable populations, i.e., pregnant women and children, and can be administered by oral and parenteral routes for weekly chemo-prevention as well as treatment of malaria, including severe malaria. Our 4-year goal for this VA Merit Review Award is to identify two lead molecules and to carry both molecules through the preclinical tests outlined here to provide sufficient information on each to warrant efficacy trials in preclinical species (beyond the budget and scope of the work proposed here) infected with P. falciparum or P. cynomolgi (a surrogate model for vivax malaria). More specifically, we hope to advance a Pharmachin, possibly late lead candidate PH-284, with a projection from the 3-position of the quinoline ring, for more advanced studies. We will also explore the amodiaquine scaffold to create a new series that we refer to as “Amodiachins” where we have moved this key structural feature to the 4-position for reasons described below. It is also our goal to advance one of these Amodiachin constructs for advanced preclinical testing as well. We believe that the combination of a relatively low developmental safety risk together with a high likelihood for therapeutic success in this endeavor (i.e., given the structural similarities to CQ and amodiaquine and the long history of their clinical use worldwide for treatment of malaria) will attract the attention of Big Pharma, the US DOD and the MMV for advancement of a fast-acting 3-substituted-pharmachin and/or an 4-position-modified amodiachin for use in humans. We hypothesize that members of these two series will serve as lead candidates for consideration as 4-aminoquinoline replacement drugs for worldwide use. Our strategic plan is to optimize these two scaffolds for: 1) anti-plasmodial activity, 2) antimalarial efficacy (in vivo mouse model), 3) low mammalian cell cytotoxicity, 4) enhanced metabolic stability (in vitro), 4) improved oral pharmacokinetics (extended T1/2 and increased AUC/exposure), and 5) improved safety/cardiotoxicity risk (diminished inhibition of herg channel, >30µM), and overall suitability to MMV’s Target Product Profiles TPP1 (treatment of uncomplicated as well as severe malaria) and TPP2 (use in chemoprevention). Our experience of working with the MMV towards the preclinical development of prodrug ELQ-331 for treatment and prophylaxis against malaria should accelerate the transformation of optimized Pharmachins and Amodiachins from concept/design to frontrunners to late leads and preclinical candidates that gain acceptance into their developmental pipeline for clinical use.

我们寻求开发一种有效的Pharmachin衍生物，具有抗恶性疟原虫和恶性疟原虫血型的活性。 间日疟原虫。我们的最终目标是开发一种廉价的抗疟疾药物，用于G6PD缺乏的患者是安全的 在最脆弱的人群中，即孕妇和儿童中，并可予管理 通过口服和非肠道途径每周进行化学预防和治疗疟疾，包括严重疟疾 疟疾。我们这个VA功绩回顾奖的四年目标是识别两个铅分子并同时携带两个 通过这里概述的临床前试验来提供关于每个分子的足够信息以保证有效性 对感染恶性疟原虫的临床前物种的试验(超出了这里提出的工作的预算和范围) 或者食蟹猴(间日疟的代用模型)。更具体地说，我们希望推进Pharmachin， 可能是后期的主要候选者PH-284，从喹啉环的3位突起，用于更高级的 学习。我们还将探索阿莫地喹支架，以创建一个新的系列，我们称之为“阿米达钦” 由于下述原因，我们已将这一关键的结构特征转移到4个位置。这也是我们的目标 以推动其中一种AModiachin结构用于先进的临床前试验。 我们认为，相对较低的发育安全风险和很高的可能性相结合 在这一努力中的治疗成功(即，鉴于CQ和阿莫地喹的结构相似，以及 它们在世界范围内用于治疗疟疾的悠久历史)将引起大制药公司的注意， 美国国防部和MMV用于发展快速作用的3-取代-药物和/或4-位修饰的药物 用于人类的阿莫地平。我们假设这两个系列的成员将作为主要候选人 考虑作为全球使用的4-氨基喹啉替代药物。我们的战略规划是优化 这两种支架用于：1)抗疟活性，2)抗疟疾效果(体内小鼠模型)，3)低 哺乳动物细胞毒性，4)提高代谢稳定性(体外)，4)改善口服药代动力学 (延长T1/2和增加AUC/暴露)，以及5)改善安全/心脏毒性风险(减少对 HERG渠道，&gt；30µM)，以及与MMV的目标产品配置文件TPP1的总体适合性(治疗不复杂的 以及严重疟疾)和TPP2(用于化学预防)。我们与MMV合作的经验 应加快治疗和预防疟疾的前药ELQ-331的临床前开发 从概念/设计到领跑者再到后领跑者的优化Pharmachins和AModiachins的转变 以及临床前候选药物，这些候选药物已进入临床使用的开发流程。