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可用于治疗疟疾的先导化合物，并通过临床前研究尽可能地推动这些化合物的发展。这些目标与健康有关的原因在于，现有治疗疟疾的药物寥寥无几，而且许多现有药物都存在临床耐药性。事实上，对现有药物的抗药性已被确定为疟疾治疗的主要困难。共同治疗已经成为解决这个问题的最好的实际解决方案。因此，这一建议的基本逻辑假设是，开发多个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解决的目标类别：阳离子通道和激酶。作为后备战略，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包括使用平行的药物化学；体外和体内测定化合物的有效性；以及体外和体内测定化合物的可用性、分布、代谢、排泄和毒性。化合物将通过应用这些方法的循环并改进模型来逐步改进，该模型定义了分子中这些特征在循环之间的整体最佳平衡。未能取得进展的复合系列将被放弃，并使用里程碑驱动模型和为复合进展定义的决策矩阵来监测进展。 这项计划的具体目标是： 1.开发五个化学类型不同的铅系列(LO)及其可能的作用机制 2.同时优化各系列抗药性恶性疟原虫的体外药效及良好的体外细胞和生化药理图谱 3.使用啮齿动物体内疗效、药代动力学和毒理学模型，优化最多五个有前景的有效铅系列(L1、L2) 4.使用体内猴的疗效、药代动力学和毒理学模型，优化最多三个有希望的晚期铅系列(L3) 5.从这些系列中选择两个临床前候选人(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