Lead optimization of DHODH inhibitors for malaria

疟疾 DHODH 抑制剂的先导优化

基本信息

批准号：
8975598
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
项目类别：
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/8975598
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 resistance Effectiveness Enzymes Etiology Event Flavin Mononucleotide Frequencies Funding Future Generations Goals Health 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 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 new therapeutic target novel novel therapeutics phase I trial physical property pre-clinical programs public-private partnership resistance mechanism scaffold screening success

项目摘要

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）：疟疾在全球90多个国家中流行，每年有超过2亿例病例和约100万例死亡。其中大部分死亡发生在撒哈拉以南非洲的儿童和孕妇中。尽管已经开发了许多有效的药物疗法，但耐药性却损害了大多数有效性，因此，如果我们要保持控制任何希望疾病。这一需求促进了不利润的公共私人伙伴关系的形成，例如疟疾风险投资（MMV）来管理新抗疟药的开发。 MMV是全球抗疟疾的最大药物开发管道，并参与了从早期发现工作到临床试验的项目。在NIH/MMV资助的项目中，我们对必需嘧啶生物合成酶二氢二烷基二氢二酸酯脱氢酶（DHODH）的抑制剂进行了高通量筛选。我们鉴定了一种有效且选择性抑制剂的三唑吡啶类化合物，并且对寄生虫具有有效的活性。随后，我们启动了一个铅优化计划，以提高效力和体内药物样性能，从而确定MMV在2011年7月作为临床前候选者提出的化合物。候选人，它代表了MMV投资组合中通过该机制运行的唯一化合物。该化合物目前正在进行GLP毒理学研究，这是如果一切顺利的话，2013年1月在MAN I阶段试验中首次开始。然而，尽管我们的计划取得了成功，只有开始I阶段试验的化合物中只有10-20％的化合物将其进行临床注册，因此临床前候选者的风险甚至更高。这现实需要我们继续努力确定当前候选人未能注册的备用候选人。该提议的目标是1）确定针对PFDHODH的1-2个其他临床前候选人。作为我们的铅优化计划的起点，我们将使用我们的HTS计划确定的新型化学脚手架，该计划由GSK的合作者提供，以及2）为当前候选人提供生物学支持，包括药物耐药性和药物协同研究。我们的团队经验丰富，在整个三唑吡啶胺的整个开发过程中都成功合作，并且具有从事全范围的铅优化活动的专业知识，包括药物化学，X射线结构确定，酶和基于细胞的测定，以及药代动力学和新陈代谢。除项目管理，监督和顾问外，MMV还将提供支持药理学和毒理学的资金，以进一步促进该项目。这些目标的成功完成将确定额外的Dhodh抑制剂，并有可能用于治疗疟疾。