Lead optimization of DHODH inhibitors for malaria

描述（由申请人提供）：疟疾在全世界90多个国家流行，每年有超过2亿例病例和约100万例死亡。其中大多数死亡发生在撒哈拉以南非洲的儿童和孕妇。虽然已经开发了一些有效的药物疗法，但抗药性损害了大多数药物的效力，因此，如果我们要保持控制这一疾病的任何希望，国际社会就必须继续确定和开发新的抗疟疾剂。这一需求推动了非营利公私伙伴关系的形成，如疟疾药物风险投资公司（MMV），以管理新抗疟药物的开发。MMV拥有全球最大的抗疟疾药物开发管道，参与的项目从早期发现工作到临床试验。在NIH/MMV资助的项目中，我们进行了一项高通量筛选，以寻找必需的嘧啶生物合成酶二氢乳清酸脱氢酶（DHODH）的抑制剂。我们确定了一种三唑并嘧啶类化合物，是疟原虫酶的有效和选择性抑制剂，也对寄生虫具有有效的活性。随后，我们启动了一项先导优化计划，以提高效价和体内药物样性质，从而鉴定出MMV在2011年7月作为临床前候选药物的化合物。这是第一个DHODH抑制剂作为候选药物，它代表了MMV产品组合中唯一通过这种机制发挥作用的化合物。该化合物目前正在进行GLP毒理学研究，作为2013年1月首次在人体I期试验的前奏，如果一切顺利。然而，尽管我们的项目取得了成功，但只有10 - 20%的开始I期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甚至更高。这 现实要求我们继续努力，在现有候选人未能登记的情况下，确定后备候选人。本提案的目标是1）确定1 - 2种靶向PfDHODH的其他临床前候选药物。作为我们的先导优化计划的起点，我们将使用我们的HTS计划或我们在GSK的合作者确定的新型化学支架，2）为当前候选药物提供生物学支持，包括耐药性和药物协同作用研究。我们的团队经验丰富，在整个三唑并嘧啶类药物的开发过程中成功合作，并拥有开展全方位先导化合物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代谢。MMV将提供资金，以支持药理学和毒理学，除了项目管理，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其他DHODH抑制剂，这些抑制剂具有治疗疟疾的潜力。

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.