Development of Antimalarial Preclinical Candidates

抗疟临床前候选药物的开发

• 批准号: 7664394
• 负责人: Rodney Kiplin Guy
• 金额: $ 107.67万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7664394
• 关键词: Antimalarials; Back; Biochemical; Cations; Clinical; Clinical Trials; Development; Drug Kinetics; Drug resistance; Equilibrium; Excretory function; Goals; Health; Human; In Vitro; Lead; Malaria; Measures; Metabolism; Methods; Modeling; Monitor; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphotransferases; Plasmodium falciparum; Property; Research Design; Resistance; Rodent; Series; Solutions; Staging; Toxic effect; Toxicology; drug candidate; improved; in vivo; lead series; pre-clinical; preclinical study; programs; quinoline; scaffold; trait

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

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铅化合物，这些化合物是治疗疟疾的候选物，并通过临床前研究尽可能向前推动这些化合物。这些目标的健康相关性在于，几乎没有可用的药物可以治疗疟疾，而许多可用的药物都具有临床抵抗。实际上，对可用药物的耐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此问题的最佳实用解决方案。因此，该提案的基本逻辑假设是，多种候选药物的发展将抑制临床抵抗的发展。该程序针对两个相对未解决的目标类别类别：阳离子通道和激酶。作为备份策略，该程序还针对具有与现有奎诺琳相同的作用机理的化合物。实现这些目标的研究设计和方法涉及使用平行药物化学；复合功效的体外和体内测量；以及在体外和体内测量复合可用性，分布，代谢，排泄和毒性的测量。通过应用这些方法的循环并完善模型，该模型将在循环之间的分子中定义这些特征的总体最佳平衡，从而逐渐改善化合物。无法进行的复合系列将被放弃，并使用具有里程碑式驱动的模型，具有具有定义的决策矩阵用于复合进展的模型。 该计划的具体目的是： 1。使用不同的化学型和推定作用机理开发五个铅序列（LO） 2。同时优化针对耐药性恶性疟原虫的疗效，并在每个系列的体外细胞和生化药理学特征上优化 3.使用体内啮齿动力，药代动力学和毒理学模型，最多优化了多达五个有前途的经过验证的铅序列（L1，L2） 4。使用体内拟邻性功效，药代动力学和毒理学模型最多优化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者（PO）