Pharmachin Optimization and Testing

我们寻求开发一种有效的Pharmachin衍生物，具有抗恶性疟原虫和疟原虫血液型的活性。 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，可安全用于G6PD缺乏的患者。 在最脆弱的人群中，即，孕妇和儿童，并可以管理 通过口服和肠胃外途径，每周进行一次化学预防和治疗疟疾，包括严重的 疟疾我们4年的目标，这个退伍军人管理局优秀评论奖是确定两个铅分子，并进行两个 通过此处概述的临床前试验，对每种分子提供足够的信息，以保证疗效 在感染恶性疟原虫的临床前种属（超出此处提出的预算和工作范围）中进行的试验 或食蟹猴疟原虫（间日疟的替代模型）。更具体地说，我们希望推进一个制药机器， 可能是晚期先导候选物PH-284，从喹啉环的3-位突出，用于更高级的 问题研究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“阿莫地喹”。 其中我们将该关键结构特征移到4位，原因如下所述。也是我们的目标 以推进这些阿莫地辛结构之一，用于先进的临床前测试。 我们认为，相对较低的发展安全风险与高可能性相结合， 为了在这种努力中获得治疗成功（即，考虑到CQ和阿莫地喹的结构相似性， 它们在全球临床上用于治疗疟疾的悠久历史）将吸引大型制药公司的注意， 美国国防部和MMV用于推进快速作用的3-取代-pharmachine和/或4-位置-修饰的 amodiachin用于人类。我们假设这两个系列的成员将作为主要候选人 考虑作为4-氨基喹啉替代药物在全球范围内使用。我们的战略计划是优化 这两种支架：1）抗疟原虫活性，2）抗疟疾功效（体内小鼠模型），3）低 哺乳动物细胞毒性，4）增强代谢稳定性（体外），4）改善口服药代动力学 （延长的T1/2和增加的AUC/暴露），和5）改善的安全性/心脏毒性风险（减少的对 herg通道，> 30 µ M），以及对MMV目标产品特征TPP1的总体适用性（治疗无并发症 以及严重疟疾）和TPP2（用于化学预防）。我们与MMV合作的经验， 用于治疗和预防疟疾前药ELQ-331的临床前开发应加速 优化的Pharmachins和Amodiachins从概念/设计到领跑者再到后来者的转变 和临床前候选人，获得认可进入其临床使用的开发管道。

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.