Development of Antimalarial Preclinical Candidates

描述（由申请人提供）：该项目的长期目标是发现多种新的先导化合物，作为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。这些目标与健康的关系在于，治疗疟疾的可用药物很少，而且其中许多可用药物存在临床耐药性。事实上，对现有药物的耐药性已被确定为治疗疟疾的主要困难。联合治疗已成为解决这一问题的最佳实用方法。因此，本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的发展。该程序针对两个相对未处理的目标类：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类药物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平行药物化学的使用；体外和体内复方药效测定；在体外和体内测量化合物的可利用性、分布、代谢、排泄和毒性。通过应用这些方法的循环，并完善定义循环之间分子中这些特征的整体最佳平衡的模型，化合物将得到逐步改进。没有进展的复合系列将被放弃，并使用一个里程碑驱动模型来监控进展，该模型带有一个已定义的复合进展决策矩阵。

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