Lead Optimization of DHODH Inhibitors for Malaria

项目描述 疟疾几千年来对人类生活产生了深远的影响，仍然是最严重的、危及生命的疾病之一。 威胁传染病，2015年造成近50万人死亡。青蒿素的有效性- 基础的综合疗法导致疟疾相关死亡人数下降。然而， 东南亚的青蒿素耐药寄生虫对疟疾控制计划构成严重威胁， 为发现新的药物疗法提供强大的管道。这一迫切需要得到以下方面的支持： 疟疾新药开发公司（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）作为 疟疾治疗的新目标。DHODH抑制剂已经成为治疗糖尿病的重要参与者。 疟疾药物发现组合，提供血液和肝脏阶段活性，以及长的人体半衰期， 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 三唑并嘧啶DSM 265通过基于靶点的高通量筛选（HTS），然后通过基于结构的 领先的优化程序。DSM 265目前处于临床开发中，并被发现在一种治疗中有效。 单剂量治疗秘鲁的恶性疟原虫患者。然而，出现了一些负债， 包括较低的间日疟原虫活性，这代表了下一代候选人的改进领域 目标是DHODH为此，在上一个赠款期，我们确定并提出了一个备用化合物 （DSM 421）;然而，由于毒性问题，DSM 421的开发被搁置 在临床前研究中发现。因此，尽管我们的计划取得了成功，但我们必须确定 来自新结构类别的DHODH抑制剂，其克服了DSM 265的已知缺点，如果有的话。 原因是它不能注册。不同种类的DHODH抑制剂也可能是有用的 针对产品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 在我们的原始HTS中鉴定出吡咯系列。我们已经确定了有效的和选择性的类似物， 与DSM 265具有交叉抗性，并且具有等同的恶性疟原虫和间日疟原虫活性。进一步引领 改善代谢稳定性的优化正在进行中。我们还发现了一些其他线索， 脚手架跳跃，定位进入全面优化。我们的团队一起努力 在DSM 265/DSM 421的开发过程中取得了成功。我们有专业知识来执行全面的 一系列的铅优化活动，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建模、基于酶和细胞的测定、药代动力学 和新陈代谢研究。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，以进一步促进项目。成功完成我们的 目的是确定新的DHODH抑制剂，有可能用于治疗疟疾。

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.