New methods in predictive metabolism
New methods in predictive metabolism
复制标题
DOI：
10.1023/a:1020881520931
复制
发表时间：
2002-05-01
影响因子：
3.5
通讯作者：
Zamora, I
中科院分区：
文献类型：
--
作者：
Boyer, S;Zamora, I
靶标验证，特别是体内靶标验证，一直是药物发现过程中的主要瓶颈之一。快速优化配体的体内药代动力学特性是提高这一众所周知的缓慢和有问题的过程的效率的基本要求之一。在优化一系列药物的药代动力学特征的过程中，代谢稳定性是一个基本要求。通常，观察到高代谢清除率，并且总是限制全身暴露、作用持续时间以及最终限制新鉴定的配体在关键的早期靶标验证工作中用于体内功效测试的有用性。解决代谢稳定性问题通常涉及代谢位点的识别。然后，这些信息被用来修改结构，以消除该网站或以某种方式（空间或电子）保护该网站。新的方法正在不断开发，以更快的速度和更准确的识别代谢物[1]，但这仍然是一个繁琐的过程，需要专业人员和仪器。虽然大多数药物发现项目必须解决代谢稳定性问题，但降低代谢清除率只是预测代谢方法的目标之一。为了减少患者间的药代动力学差异，理想情况下，任何药物样分子的清除应通过几种途径进行，包括代谢以及肾脏和胆汁排泄。同样，对单一代谢途径或蛋白质的依赖性也可能是变异的来源，因此清除的代谢组分也应尽可能多样化。因此，用于预测代谢的新工具不仅需要解决修复高清除率的代谢位点的问题，而且还需要预测代谢途径，即异源代谢途径。
Target validation, and particularly in vivo target validation, has always been one of the major bottlenecks in the process of drug discovery. Quickly optimising ligands for their in vivo pharmacokinetic properties is one of the basic requirements for enhancing the efficiency of this notoriously slow and problematic process.In the process of optimising the pharmacokinetic profile of a series, metabolic stability is a basic requirement. Often, high metabolic clearance is observed and invariably limits the systemic exposure, duration of action and ultimately the usefulness of newly identified ligands for in vivo efficacy testing in the critical early target validation efforts. Addressing metabolic stability problems most often involves identification of the site of metabolism. This information is then used to modify the structure in a way that will eliminate the site or protect the site in some way (steric or electronic). New methods are being developed constantly to identify metabolites with greater speed and accuracy [1], however this is still a tedious process requiring specialized personnel and instrumentation. Whilst most Drug Discovery projects have to address issues of metabolic stability, reducing metabolic clearance is only one of the goals of predictive metabolism methods. For reducing patient-to-patient pharmacokinetic variation, clearance of any drug–like molecule should ideally be via several pathways, including metabolism and renal and biliary excretion. Likewise, dependence on a single metabolic pathway or protein can also be a source of variation and the metabolic component of clearance should therefore also be as diverse as possible. Thus new tools for predicting metabolism need to address not only issues of metabolic site to repair high clearance but also need to predict routes of metabolism, ie, iso-