Lead Optimization of DHODH Inhibitors for Malaria

疟疾 DHODH 抑制剂的先导优化

• 批准号: 10179303
• 负责人: Margaret A. Phillips
• 金额: $ 72.69万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10179303
• 关键词: ADME Study; Acids; Affect; African; Anabolism; Antimalarials; Area; Artemisinins; Asia; Back; Binding; Biological; Biological Assay; Blood; Cells; Cessation of life; Chemicals; Chemoprevention; Child; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Communicable Diseases; DHODH gene; Development; Dihydroorotate dehydrogenase; Disease; Dose; Drug Combinations; Drug Kinetics; Drug Synergism; Drug resistance; Effectiveness; Enzymes; Financial Support; Flavin Mononucleotide; Fostering; Frequencies; Funding; Goals; Grant; Half-Life; Human; In Vitro; Insecticides; Ion Channel; Life; Life Cycle Stages; Liver; Malaria; Malaria Vaccines; Mammalian Cell; Medicine; Metabolic; Metabolism; Mind; Mitochondria; Modeling; Molecular Conformation; Parasite resistance; Parasites; Patients; Peru; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Population; Positioning Attribute; Property; Pyrimidine; Pyrimidine Nucleotides; Pyrroles; Resistance; Resistance development; Resistance profile; Roentgen Rays; SCID Mice; Series; Source; Structure; Testing; Toxic effect; United States National Institutes of Health; Validation; Work; analog; base; chemotherapeutic agent; clinical development; clinical risk; combat; comparative efficacy; design; drug candidate; drug discovery; efficacy testing; experience; high throughput screening; improved; in vivo; inhibitor/antagonist; lead optimization; metabolic abnormality assessment; mortality; mouse model; multidisciplinary; next generation; novel; novel therapeutics; pre-clinical; preclinical development; preclinical study; programs; resistance allele; resistance mechanism; safety assessment; scaffold; success

Project Description Malaria has profoundly affected human lives for thousands of years and remains one of the most serious, life- threatening infectious diseases, causing nearly 0.5 million deaths in 2015. The effectiveness of artemisinin- based combination therapies has led to declines in malaria-related deaths. However, the emergence of artemisinin-resistant parasites in SE Asia poses a serious threat to malaria control programs, necessitating that a robust pipeline be supported for the discovery of new drug therapies. This urgent need is fostered by Medicines for Malaria Venture (MMV), which supports projects from early discovery work to clinical trials. Through a NIH/MMV funded project our team clinically validated dihydroorotate dehydrogenase (DHODH) as a new target for the treatment of malaria. DHODH inhibitors have since emerged as important players in the malaria drug discovery portfolio, providing both blood and liver stage activity, and long human half-life that supports single dose cure or once weekly chemoprevention. In past fund periods, we identified the triazolopyrimidine DSM265 by a target-based high throughput screen (HTS) followed by a structure-based lead optimization program. DSM265 is currently in clinical development and was found to be efficacious in a single dose for the treatment of P. falciparum patients in Peru. However, several liabilities have emerged, including lower P. vivax activity, which represent areas for improvement in next generation candidates targeting DHODH. To that end in the last grant period we identified and advanced a backup compound (DSM421) from the same series; however, development of DSM421 was put on hold due to toxicity issues identified in preclinical studies. Thus, despite the success of our program it is essential that we identify DHODH inhibitors from novel structural classes that overcome the known liabilities of DSM265 if for any reason it fails to make it to registration. Different classes of DHODH inhibitors could potentially also be useful for different product profiles within the portfolio. With these goals in mind, we are currently optimizing a pyrrole series identified in our original HTS. We have identified potent and selective analogs that do not share cross-resistance with DSM265 and which have equivalent P. falciparum and P. vivax activity. Further lead optimization to improve metabolic stability is underway. We have also identified a number of other leads by scaffold hopping that are positioned to enter full-scale optimization. Our team has worked together successfully throughout the development of DSM265/DSM421. We have the expertise to carry out the full range of lead optimization activities, including medicinal chemistry, X-ray structure determination, structure- based modeling through a collaboration with Schrodinger, enzyme and cell-based assays, pharmacokinetics and metabolism studies. Additionally, MMV will provide extra financial support in key areas and will provide project management, oversight and advisors to further facilitate the project. Successful completion of our aims will identify novel DHODH inhibitors with the potential to be advanced for the treatment of malaria.

项目描述 疟疾已经深远影响了人类的生命已有数千年了，并且仍然是最严重的生活之一 威胁传染病，2015年造成近50万人死亡。青蒿素的有效性 基于疟疾相关的死亡的基于联合疗法导致下降。但是，出现了 东南亚亚洲的抗甲半氨会抗性寄生虫对疟疾控制计划构成了严重威胁，需要 为发现新药物疗法而支持强大的管道。这种迫切的需求是由 疟疾风险投资（MMV），它支持从早期发现工作到临床试验的项目。 通过NIH/MMV资助的项目，我们的团队临床验证的二氢二氢酶脱氢酶（DHODH）作为 治疗疟疾的新目标。此后，Dhodh抑制剂已成为重要参与者 疟疾药物发现组合，提供血液和肝脏阶段活动，以及长期的人类半衰期 支持单剂量治疗或每周一次的化学预防。在过去的基金期间，我们确定了 基于目标的高吞吐量屏幕（HTS），然后是基于结构的三唑嘧啶DSM265 线索优化程序。 DSM265目前正在临床开发中，发现在 单剂量用于治疗秘鲁的恶性疟原虫患者。但是，已经出现了几项责任， 包括较低的Vivax活动，代表下一代候选人的改进领域 针对Dhodh。为此，在最后一个赠款期间，我们确定并提出了备份化合物 （DSM421）来自同一系列；但是，由于毒性问题，DSM421的开发被搁置 在临床前研究中确定。因此，尽管我们计划取得了成功，但我们必须确定 如果有任何， 原因无法进行注册。不同类别的Dhodh抑制剂也可能有用 对于投资组合中的不同产品配置文件。考虑到这些目标，我们目前正在优化 吡咯系列在我们的原始HTS中确定。我们已经确定了不共享的有力和选择性类似物 与DSM265的交叉抗性，具有等效的恶性疟原虫和假子活性。进一步的领导 正在进行提高代谢稳定性的优化。我们还通过 脚手架跳跃可以进入全尺度优化。我们的团队共同努力 在整个DSM265/DSM421的开发过程中成功。我们有专业知识来完成完整的 铅优化活性的范围，包括药物化学，X射线结构确定，结构 - 通过与Schrodinger，酶和基于细胞的测定法，药代动力学合作进行建模 和代谢研究。此外，MMV将在关键领域提供额外的财政支持，并将提供 项目管理，监督和顾问，以进一步促进该项目。成功完成我们 AIMS将鉴定出新型的Dhodh抑制剂，并有可能用于治疗疟疾的潜力。