Lead optimization of DHODH inhibitors for malaria

疟疾 DHODH 抑制剂的先导优化

• 批准号: 8601042
• 负责人: Margaret A. Phillips
• 金额: $ 59.54万
• 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/8601042
• 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(申请人提供)：疟疾在全球90多个国家流行，每年记录的病例超过2亿例，死亡约100万人。其中大多数死亡发生在撒哈拉以南非洲的儿童和孕妇身上。虽然已经开发了一些有效的药物疗法，但耐药性损害了MOST的有效性，因此，如果我们要保持控制这种疾病的任何希望，国际社会就有必要继续确定和开发新的抗疟疾药物。这种需求推动了非营利性公私伙伴关系的形成，如疟疾药物风险投资(MMV)，以管理新的抗疟疾药物的开发。MMV拥有世界上最大的抗疟疾药物开发流水线，并参与了从早期发现工作到临床试验的各种项目。在NIH/MMV资助的一个项目中，我们对必需的嘧啶生物合成酶二氢罗酸脱氢酶(DHODH)的抑制剂进行了高通量筛选。我们鉴定了一类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，并且对寄生虫也有很强的活性。随后，我们启动了一项先导优化计划，以提高效力和体内类药物特性，从而确定了一种化合物，该化合物于2011年7月被MMV提升为临床前候选化合物。这是第一个被提升为候选药物的DHODH抑制剂，它代表了MMV产品组合中唯一通过这一机制发挥作用的化合物。如果一切顺利，该化合物目前正在进行GLP毒理学研究，作为2013年1月开始第一阶段MAN试验的前奏。然而，尽管我们的计划取得了成功，但只有10%-20%的开始第一阶段试验的化合物将进入临床注册，因此临床前候选药物的风险更高。这 现实情况要求，如果现任候选人未能登记，我们必须继续努力确定后备候选人。该提案的目标是：1)确定另外1-2个针对PfDHODH的临床前候选药物。作为我们的领先优化计划的起点，我们将使用我们的HTS计划确定的新型化学支架，包括：1)由我们在GSK的合作者确定的；2)为当前的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，在三唑并嘧啶类化合物的整个开发过程中成功合作，并拥有开展全方位铅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，此外还将提供项目管理、监督和顾问，以进一步促进该项目。这些目标的成功完成将确定更多的DHODH抑制剂，这些药物有可能被推进用于治疗疟疾。