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.

我们试图开发一种潜在的Pharmachin衍生物，其活性针对恶性疟原虫和P. Vivax。我们的最终目标是开发一个廉价的反车辆，该反车辆可安全用于G6PD默认 个人，以及最脆弱的人群，即孕妇和儿童，可以管理 通过口服和父母的路线，用于每周进行化学预防以及对疟疾的治疗，包括严重 疟疾。我们获得VA功绩审查奖的四年目标是确定两个主要分子，并携带这两种分子 通过此处概述的临床前测试分子，以提供有关每个测试的足够信息，以保证效率 临床前物种的试验（此处提出的作品的预算和范围）感染了恶性疟原虫 或P. cynomolgi（可为疟疾的替代模型）。更具体地说，我们希望推进Pharmachin， 可能是后期的铅候选pH-284，带有喹啉环3位的投影，用于更先进 研究。我们还将探索Amodiaquine脚手架，以创建一个我们称为“ Amodiacochins”的新系列 由于下文所述，我们将此关键结构特征移至4位。这也是我们的目标 为了推进这些阿莫迪亚钦构建体之一，以进行晚期临床前测试。 我们认为，相对较低的发育安全风险以及很有可能的结合 为了在这项努力中进行热成功（即，给定与CQ和Amodiaquine的结构相似性以及 全世界在疟疾治疗的临床用途的悠久历史）将吸引大型药物的注意 US DOD和MMV，用于进步的3-取代 - 帕尔玛金和/或4位修饰的MMV Amodiachin用于人类。我们假设这两个系列的成员将担任主要候选人 考虑到4-氨基喹啉替代药物用于全球使用。我们的战略计划是优化 这两个脚手架的脚手架：1）抗质量活性，2）抗疟疾效率（体内小鼠模型），3）低 哺乳动物细胞细胞毒性，4）增强的代谢稳定性（体外），4）改善口服药代动力学 （延长T1/2和增加的AUC/暴露），以及5）改善安全/心脏毒性风险（抑制减少了 HERG通道，> 30µm），以及MMV的目标产品概况TPP1的总体适用性（简单处理） 以及严重的疟疾）和TPP2（用于化学预防）。我们与MMV合作的经验 前药ELQ-331的临床前开发用于治疗和预防疟疾，应加速 优化的Pharmachis和Amodiochins从概念/设计转换为领跑者到较晚的潜在客户 以及临床前的候选人，他们将接受临床使用的发育渠道接受。