Optimization of pyrimidinyl prodrugs (PYPs) for malaria chemotherapy

用于疟疾化疗的嘧啶基前药 (PYP) 的优化

• 批准号: 7934795
• 负责人: PRADIPSINH K. RATHOD
• 金额: $ 79.4万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934795
• 关键词: Acids; Active Sites; Anabolism; Antimalarials; Antimetabolites; Basic Science; Binding; Biochemistry; Biological; Biological Assay; Biological Availability; Bolus Infusion; Canis familiaris; Carboxylic Acids; Cell Death; Cells; Cessation of life; Chemistry; Clinical; Collaborations; Consultations; Continuous Infusion; DNA; Data; Deoxyuridine; Development; Dihydrofolate Reductase; Dose; Drug Controls; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Erythrocytes; Folic Acid Antagonists; Goals; Half-Life; Human; Hydrolase; In Vitro; Individual; Lead; Libraries; Liver; Malaria; Mammalian Cell; Measurement; Modification; Monitor; Morbidity - disease rate; Mus; Nonprofit Organizations; Oral; Orotate Phosphoribosyltransferase; Parasites; Pathway interactions; Pharmaceutical Preparations; Plasmodium falciparum; Preparation; Process; Prodrugs; Production; Property; Proteins; Pyrimethamine; Pyrimidine; Pyrimidines; Rattus; Reaction; Recrudescences; Resistance; Safety; Serum; Staging; Technology; Testing; Thymidine Monophosphate; Thymidylate Synthase; Tissues; Toxic effect; Toxicology; Translational Research; United States National Institutes of Health; Uridine; Variant; Work; base; chemical release; chemotherapy; clinical toxicology; combinatorial; cost; drinking water; drug candidate; drug development; drug metabolism; fluoropyrimidine; improved; in vivo; interest; killings; member; mimicry; mortality; mouse model; novel; nucleotide metabolism; pre-clinical; preclinical study; programs; response; s-trioxane; safety study; thymidylate synthase-dihydrofolate reductase

yrimidinyl Prodrugs for Malaria Significance: Malaria parasites infect about a billion individuals and cause up to 2 million deaths per year. The present application is to support translational research leading to the development of a novel and more effective drug strategy to help reduce or eliminate morbidity and mortality from malaria. Promising hit: Over the last two decades, the PI has systematically considered multiple ways to attack malarial thymidylate synthase with nanomolar-level enzyme inhibitors active in whole cell assays. Based on practical issues related to potency, safety, cost of goods, low propensity for resistance, and lack of cross-resistance to other antimalarials, 6-carboxy-2,4-dioxo-5- fluoropyrimidine (5-fluoroorotate or PYP1) stands out as the best hit. It has an EC50 of 5 nM against all malaria parasites tested and is 1,000 less toxic to mammalian cells. Resistance does not occur at relevant doses. Mouse models for malaria and quantitative in vitro studies of safety versus potency suggest that PYP1, as is, has comparable selectivity to pyrimethamine. It can be even better with some improved pharmacokinetics and controlled drug release. Paths to a drug candidate: The PI proposes a hit-to-lead (HTL) plan to deliver a candidate for advancement to preclinical studies. The project will have the following specific aims: (i) Based on recent advances in prodrug chemistry, a focused combinatorial library will be generated with the aim of selective enzyme-based release of active molecule in the parasite but not host cells. (ii) Based on endoperoxide chemistry, trioxanes and tetraoxane derivatives of PYP1 will be made to selectively release the active carboxylic acids in the parasite (iii) Cell-based screens and toxicity panels will be implemented and used to identify appropriate PYP1 precursors and to prioritize them (iv) ADME and PK studies in rats and mice will be used to optimize advancing molecules. (v) The team will seek synergy partners, test for avoidance of resistance and cross-resistance, perform a 5-day rat toxicology and a dog PK study. Concluding goal: Based on 15-years of NIH basic research and the present translational effort, we will nominate a drug candidate and a backup compound. In consultation with NIH program staff, federal or non-profit organizations will be approached to carry the nominated compound through advanced pre-clinical toxicology and formulation process in preparation for first-in-human (FIH) use.

Yrimidinyl前药的疟疾 意义：疟疾寄生虫感染大约十亿人，并造成多达200万人死亡 每年。目前的应用是支持转化研究，导致发展 一种新颖，更有效的药物策略，以帮助降低或消除发病率和死亡率 来自疟疾。 有希望的热门：在过去的二十年中，PI系统地考虑了多种方法 用纳摩尔级酶抑制剂在全细胞中攻击疟疾胸苷酸合酶 测定。基于与效力，安全性，商品成本相关的实际问题，低倾向 耐药性，缺乏对其他抗疟药的交叉耐药性，6-羧基-2,4-dioxo-5- 氟吡啶胺（5-氟甲前或PYP1）是最佳打击。它的EC50为5 nm 针对所有测试的疟疾寄生虫，对哺乳动物细胞的毒性减少了1,000。阻力确实如此 不以相关剂量发生。小鼠模型的疟疾和安全性研究 与效力相对于效力表明，PYP1与乙胺胺具有可比的选择性。可以 通过一些改进的药代动力学和受控药物释放，甚至更好。 候选药物的途径：PI提出了一项命中率（HTL）计划，以交付候选人 临床前研究的进步。该项目将具有以下具体目标： （i）基于前药化学的最新进展，重点的组合库将是 生成的目的是基于选择性酶的活性分子释放 寄生虫，但不是宿主细胞。 （ii）基于过氧化物化学，三氧烷和四氧烷的衍生物将是PYP1的 制作以选择性地释放寄生虫中的活性羧酸 （iii）将实施基于细胞的筛选和毒性面板，并用于确定适当的 PYP1前体并确定优先级 （iv）大鼠和小鼠的ADME和PK研究将用于优化前进的分子。 （v）团队将寻求协同合作伙伴，测试避免抵抗和越野抗性， 进行5天的大鼠毒理学和狗PK研究。 总结目标：基于NIH基础研究的15年和当前的翻译工作， 我们将提名候选药物和备用化合物。与NIH计划协商 将要求工作人员，联邦或非营利组织携带提名的化合物 通过先进的临床前毒理学和制定过程，为第一人类做准备 （fih）使用。