Lead optimization of DHODH inhibitors for malaria

疟疾 DHODH 抑制剂的先导优化

• 批准号: 8440181
• 负责人: Margaret A. Phillips
• 金额: $ 63.63万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440181
• 关键词: ADME Study; Acids; Address; Africa South of the Sahara; Anabolism; Aniline; Antimalarials; Back; Binding; Biological; Biological Assay; Cells; Cessation of life; Chemicals; Chemistry; Child; Clinical; Clinical Research; Clinical Trials; Communities; Country; Data; Death Records; Deltastab; Development; Dihydroorotate Dehydrogenase Inhibitor; Dihydroorotate dehydrogenase; Drug Kinetics; Drug Targeting; Drug resistance; Effectiveness; Enzymes; Etiology; Event; Flavin Mononucleotide; Frequencies; Funding; Future; Generations; Goals; Human; In Vitro; Ion Channel; Knowledge; Lead; Learning; Malaria; Medicine; Metabolism; Mitochondria; Molecular; Mus; Organism; Parasite resistance; Parasites; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology and Toxicology; Pharmacotherapy; Phase I Clinical Trials; Plasmodium; Plasmodium falciparum; Pregnant Women; Property; Pyrimidine; Pyrimidine Nucleotides; Pyrroles; Resistance; Risk; Rodent; Roentgen Rays; SCID Mice; Safety; Source; Structure; Testing; Toxicology; United States National Institutes of Health; Work; base; cell killing; chemotherapeutic agent; chemotherapy; combat; design; dihydroorotate; disorder control; drug candidate; drug development; drug discovery; efficacy testing; experience; high throughput screening; improved; in vivo; indoline; inhibitor/antagonist; insight; interest; killings; man; meetings; mouse model; novel; physical property; pre-clinical; programs; public health relevance; public-private partnership; resistance mechanism; scaffold; screening; success

DESCRIPTION (provided by applicant): Malaria is endemic in over 90 countries world-wide with over 200 million cases and ~ 1million deaths recorded yearly. Of these most of the deaths occur in children and pregnant woman in Sub-Saharan Africa. While a number of effective drug therapies have been developed, drug resistance has compromised the effectiveness of most, and thus it is necessary for the world community to continue to identify and develop new anti-malarial agents if we are to maintain any hope of controlling the disease. This need has fueled the formation of not for profit public private partnerships such as Medicines for Malaria Venture (MMV) to manage the development of new antimalarials. MMV has the largest drug development pipeline for anti malarials world-wide and is involved in projects spanning from early discovery work to clinical trials. In an NIH/MMV funded project we performed a high throughput screen for inhibitors of the essential pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH). We identified a triazolopyrimidine class of compounds that were potent and selective inhibitors of the Plasmodium enzyme, and which also had potent activity against the parasite. We subsequently initiated a lead optimization program to improve both potency and in vivo drug-like properties, leading to the identification of a compound that was advanced by MMV as a preclinical candidate in July 2011. This is the first DHODH inhibitor to be advanced as a candidate and it represents the only compound in MMV's portfolio that operates through this mechanism. The compound is currently undergoing GLP toxicology studies as a prelude to starting first in man Phase I trials in Jan 2013, if all goes well. However despite the success of our program only 10-20% of compounds that begin Phase I trials will make it to clinical registration, and thus the risk to a preclinical candidate is even higher. This reality necessitates that we continue efforts to identify a back-up candidate should the current candidate fail to make it to registration. The goals of this proposal are to 1) identify 1-2 additional preclinical candidates targeting PfDHODH. As starting points for our lead optimization program we will use novel chemical scaffolds identified by our HTS program of by that of our collaborators at GSK, and 2) to provide biological support for the current candidate, including drug resistance and drug synergy studies. Our team is experienced, has worked together successfully throughout the development of the triazolopyrimidines, and has the expertise to carry out the full range of lead optimization activities, including medicinal chemistry, X- ray structure determination, enzyme and cell-based assays, and pharmacokinetics and metabolism. MMV will provide funds to support pharmacology and toxicology, in addition to project management, oversight and advisors to further facilitate the project. Successful completion of these aims will identify additional DHODH inhibitors with the potential to be advanced for the treatment of malaria.

描述（由申请人提供）：疟疾在全世界 90 多个国家流行，每年有超过 2 亿病例和约 100 万人死亡。其中大部分死亡发生在撒哈拉以南非洲地区的儿童和孕妇。虽然已经开发出许多有效的药物疗法，但耐药性已经损害了大多数疗法的有效性，因此，如果我们要保持控制疟疾的希望，国际社会有必要继续识别和开发新的抗疟疾药物。疾病。这种需求推动了非营利性公私合作伙伴关系的形成，例如疟疾风险投资公司 (MMV)，以管理新抗疟药的开发。 MMV 拥有全球最大的抗疟疾药物开发渠道，参与从早期发现工作到临床试验的项目。在 NIH/MMV 资助的项目中，我们对必需的嘧啶生物合成酶二氢乳清酸脱氢酶 (DHODH) 的抑制剂进行了高通量筛选。我们鉴定出三唑并嘧啶类化合物，它们是疟原虫酶的有效和选择性抑制剂，并且对寄生虫也具有有效的活性。随后，我们启动了一项先导化合物优化计划，以提高效力和体内药物样特性，最终确定了 MMV 于 2011 年 7 月作为临床前候选药物推进的化合物。这是第一个作为药物推进的 DHODH 抑制剂。它是 MMV 投资组合中唯一通过这种机制运作的化合物。该化合物目前正在进行 GLP 毒理学研究，如果一切顺利的话，将作为 2013 年 1 月开始首次人体 I 期试验的前奏。然而，尽管我们的计划取得了成功，但开始 I 期试验的化合物中只有 10-20% 能够进入临床注册，因此临床前候选药物的风险甚至更高。这 现实情况表明，如果当前候选人未能完成登记，我们必须继续努力寻找后备候选人。该提案的目标是 1) 确定 1-2 个额外的针对 PfDHODH 的临床前候选药物。作为我们的先导化合物优化计划的起点，我们将使用由我们的 HTS 计划（由 GSK 的合作者的 HTS 计划确定）确定的新型化学支架，2) 为当前候选药物提供生物支持，包括耐药性和药物协同研究。我们的团队经验丰富，在三唑并嘧啶的整个开发过程中成功合作，并拥有开展全方位先导化合物优化活动的专业知识，包括药物化学、X 射线结构测定、酶和细胞分析以及药代动力学和新陈代谢。 MMV 将提供资金支持药理学和毒理学，以及项目管理、监督和顾问以进一步促进该项目。成功完成这些目标将确定更多有潜力用于疟疾治疗的 DHODH 抑制剂。