Further development of our Drug Discovery Platform FORECASTER and its application to the design, synthesis and biological evaluation of prolyl oligopeptidase Inhibitors

我们的药物发现平台 FORECASTER 的进一步开发及其在脯氨酰寡肽酶抑制剂的设计、合成和生物学评价中的应用

• 批准号: 387267-2009
• 负责人: Moitessier, Nicolas
• 金额: $ 5.47万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Collaborative Research and Development Grants
• 财政年份: 2009
• 资助国家: 加拿大
• 起止时间: 2009-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=442800
• 关键词: Further; development; our; Drug; Discovery

Prolyl Oligopeptidase (POP) inhibition is a highly promising strategy for the treatment of Alzheimer's disease and POP inhibitors as drug candidates are to be developed. Moitessier and co-workers have recently reported a potent, permeant and highly selective POP inhibitor. However, its stability and pharmacokinetic profile need to be improved. A large number of drug discovery and development projects fail at the late development stages due to poor pharmacokinetic profiles. Integrating the evaluation of absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) of potential candidate drugs early in the drug discovery process is expected to significantly reduce this failure rate. IIi this context, predicting the ADME-Tox profile using computational methods has been seen as a high-throughput and inexpensive option that could complement low to medium throughput in vitro or in vivo assays. Moitessier and co-workers have developed a sophisticated platform of programs (FORECASTER) which performs virtual screening, docking and more (www.fitted.ca). In this research, we plan to combine our complementary expertise in organic synthesis, medicinal chemistry, metabolism and software development to 1. develop accurate in silico methods that predict the cytochrome P450-mediated metabolism and P450 inhibition and implement them in our platform FORECASTER; 2. apply this suite of programs to the development of improved POP inhibitors.

脯氨酰寡肽酶（POP）抑制是治疗阿尔茨海默病的一种非常有前途的策略，POP抑制剂作为候选药物有待开发。Moitessier及其同事最近报道了一种有效的、渗透性的和高度选择性的POP抑制剂。然而，其稳定性和药代动力学特征需要改进。大量的药物发现和开发项目在后期开发阶段由于不良的药代动力学特征而失败。在药物发现过程的早期整合对潜在候选药物的吸收、分布、代谢、排泄和毒性（ADME-Tox）的评估，预计将显著降低这种失败率。在这种情况下，使用计算方法预测ADME-Tox谱已被视为高通量和廉价的选择，其可以补充低至中等通量的体外或体内测定。Moitessier和同事们开发了一个复杂的程序平台（FORECASTER），可以执行虚拟筛选，对接等（www.fitted.ca）。在这项研究中，我们计划联合收割机我们互补的专业知识，在有机合成，药物化学，代谢和软件开发，以1。开发准确的预测细胞色素P450介导的代谢和P450抑制的计算机方法，并在我们的平台FORECASTER中实现它们; 2.将这套程序应用于开发改进的POP抑制剂。