Pharmachin Optimization and Testing

Pharmachin 优化和测试

• 批准号: 10620168
• 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/10620168
• 关键词: 4-aminoquinoline; Acceleration; 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 Metabolism Induction; Drug toxicity; Exhibits; Fever; Future; Glucosephosphate Dehydrogenase Deficiency; Goals; Health; Hemolytic Anemia; Human; In Vitro; Individual; Infection; Knowledge; Lead; Learning; Legal patent; Malaria; Mammalian Cell; Mannich Bases; Mediating; Medical; Mefloquine; Metabolic; Microsomes; Modeling; Modification; Multi-Drug Resistance; Mus; Neurologic; Oral; Oral Administration; Parasites; Persons; 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; 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 action; 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 blocking; 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药物衍生物与活性对抗血液形式的恶性疟原虫和疟原虫。