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 数千年来，疟疾深刻影响着人类的生活，并且仍然是最严重的生命威胁之一。 威胁传染病，2015 年导致近 50 万人死亡。青蒿素的有效性 联合疗法导致疟疾相关死亡人数下降。然而，出现 东南亚的青蒿素抗药性寄生虫对疟疾控制计划构成严重威胁，因此需要 支持强大的管道以发现新的药物疗法。这种迫切的需求是由 Medicines for Malaria Venture (MMV)，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了二氢乳清酸脱氢酶 (DHODH) 治疗疟疾的新目标。 DHODH 抑制剂已成为该领域的重要参与者。 疟疾药物发现组合，提供血液和肝脏阶段活性，以及​​较长的人体半衰期， 支持单剂量治愈或每周一次化学预防。在过去的基金期间，我们确定了 三唑并嘧啶 DSM265 通过基于靶标的高通量筛选 (HTS)，然后进行基于结构的筛选 领先优化计划。 DSM265 目前正处于临床开发阶段，并被发现在多种疾病中有效 单剂量用于治疗秘鲁的恶性疟原虫患者。然而，一些负债已经出现， 包括较低的间日疟原虫活性，这代表了下一代候选者需要改进的领域 靶向DHODH。为此，在上一个资助期内，我们确定并改进了一种备用化合物 (DSM421) 来自同一系列；然而，DSM421的开发由于毒性问题而被搁置 临床前研究中确定。因此，尽管我们的计划取得了成功，但我们必须确定 来自新型结构类别的 DHODH 抑制剂克服了 DSM265 的已知缺点（如果有的话） 未能成功注册的原因。不同类别的 DHODH 抑制剂也可能有用 适用于产品组合中的不同产品概况。考虑到这些目标，我们目前正在优化 我们最初的 HTS 中确定了吡咯系列。我们已经鉴定出有效且选择性的类似物，它们不具有相同的特征 与 DSM265 具有交叉耐药性，且具有同等的恶性疟原虫和间日疟原虫活性。进一步领先 旨在提高代谢稳定性的优化正在进行中。我们还确定了一些其他线索 支架跳跃已定位进入全面优化。我们的团队一起努力 成功完成了 DSM265/DSM421 的开发。我们拥有专业知识来进行全面的 一系列先导化合物优化活动，包括药物化学、X 射线结构测定、结构- 通过与薛定谔合作进行基于模型、酶和细胞分析、药代动力学 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。顺利完成我们的 目标将确定新型 DHODH 抑制剂，有可能进一步用于疟疾的治疗。