Development of Antimalarial Preclinical Candidates

描述（由申请人提供）：该项目的广泛，长期目标是发现多种新的先导化合物，这些化合物是治疗疟疾的候选药物，并通过临床前研究尽可能地推动这些化合物的发展。这些目标与健康相关，因为治疗疟疾的药物很少，而且许多现有药物在临床上具有抗药性。事实上，对现有药物的抗药性已被确定为治疗疟疾的主要困难。共同治疗已成为解决这一问题的最佳实际解决方案。因此，该提案的基本逻辑假设是，开发多种候选药物将能够抑制临床耐药性的发展。该计划针对两个相对未解决的目标类别：阳离子通道和激酶。作为备用策略，该计划还针对与现有喹啉具有相同作用机制的化合物。实现这些目标的研究设计和方法涉及使用平行药物化学;化合物疗效的体外和体内测量;以及化合物可用性、分布、代谢、排泄和毒性的体外和体内测量。化合物将通过应用这些方法的循环和改进模型来逐步改进，该模型定义了循环之间分子中这些性状的总体最佳平衡。未能进展的化合物系列将被放弃，并使用具有化合物进展定义决策矩阵的里程碑驱动模型监测进展。 该方案的具体目标是： 1.开发具有不同化学型和假定作用机制的五个铅系列（LO） 2.同时优化每个系列在体外抗耐药恶性疟原虫的功效以及有利的体外细胞和生化药理学特征 3.使用体内啮齿动物疗效、药代动力学和毒理学模型优化多达5个有前景的经验证的电极导线系列（L1、L2） 4.使用体内猿猴疗效、药代动力学和毒理学模型优化多达三个有前景的晚期先导化合物系列（L3） 5.从这些系列中选择两个临床前候选药物（PO）

DESCRIPTION (provided by applicant): The broad, long term goals of this project are to discover multiple new lead compounds that are candidates for the treatment of malaria and to push these compounds as far forward as possible through preclinical studies. The health relatedness of these goals lies in the fact that there are few available drugs to treat malaria and many of those that are available are subject to clinical resistance. In fact, resistance to available drugs has been identified as the primary difficulty in the treatment of malaria. Co-therapy has emerged as the best practical solution to this problem. Therefore, the basic logical assumption of this proposal is that the development of multiple drug candidates will enable the suppression of the development of clinical resistance. This program targets two relatively unaddressed target classes: cation channels and kinases. As a back up strategy, the program also targets compounds with the same mechanism of action as existing quinolines. The research design and methods for achieving these goals involves the use of parallel medicinal chemistry; in vitro and in vivo measures of compound efficacy; and in vitro and in vivo measures of compound availability, distribution, metabolism, excretion, and toxicity. Compounds will be incrementally improved by applying cycles of these methods and refining the model that defines the overall best balance of these traits in a molecule between cycles. Compound series that fail to progress will be abandoned and progression monitored using a milestone driven model with a defined decision matrix for compound progression. The specific aims of this program are: 1. Develop five lead series (LO) with divergent chemotypes and presumptive mechanisms of action 2. Simultaneously optimize efficacy against drug resistant P. falciparum in vitro and favorable in vitro cellular and biochemical pharmacological profiles for each series 3. Optimize up to five promising validated lead series (L1, L2) using in vivo rodent efficacy, pharmacokinetic, and toxicology models 4. Optimize up to three promising late stage lead series (L3) using in vivo simian efficacy, pharmacokinetic, and toxicology models 5. Select two preclinical candidates (PO) from these series