Lead optimization of DHODH inhibitors for malaria

描述（由申请人提供）：疟疾在全球90多个国家流行，每年记录的病例超过2亿，死亡人数约100万。其中大多数死亡发生在撒哈拉以南非洲的儿童和孕妇中。虽然已经开发了一些有效的药物治疗方法，但耐药性已经损害了大多数药物的有效性，因此，如果我们要保持控制疟疾的任何希望，国际社会就有必要继续确定和开发新的抗疟疾剂。这一需求推动了非营利性公私伙伴关系的形成，例如疟疾药物企业（MMV），以管理新的抗疟疾药物的开发。MMV拥有世界上最大的抗疟疾药物开发管道，并参与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羟酸脱氢酶（DHODH）的抑制剂进行了高通量筛选。我们发现了三唑嘧啶类化合物，它们是疟原虫酶的有效和选择性抑制剂，并且对寄生虫也有有效的活性。随后，我们启动了一项先导优化计划，以提高效力和体内药物样特性，并于2011年7月鉴定出MMV公司开发的一种化合物作为临床前候选药物。这是第一个作为候选的DHODH抑制剂，它代表了MMV组合中唯一通过这种机制起作用的化合物。该化合物目前正在进行GLP毒理学研究，如果一切顺利，将于2013年1月在人体进行第一阶段试验。然而，尽管我们的项目取得了成功，但只有10-20%开始I期试验的化合物能够进入临床注册，因此临床前候选药物的风险甚至更高。这

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.