Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, the Netherlands.
Med Res Rev. 2014 Jul;34(4):856-92. doi: 10.1002/med.21307. Epub 2014 Feb 18.
A vast number of marketed drugs act on G protein-coupled receptors (GPCRs), the most successful category of drug targets to date. These drugs usually possess high target affinity and selectivity, and such combined features have been the driving force in the early phases of drug discovery. However, attrition has also been high. Many investigational new drugs eventually fail in clinical trials due to a demonstrated lack of efficacy. A retrospective assessment of successfully launched drugs revealed that their beneficial effects in patients may be attributed to their long drug-target residence times (RTs). Likewise, for some other GPCR drugs short RT could be beneficial to reduce the potential for on-target side effects. Hence, the compounds' kinetics behavior might in fact be the guiding principle to obtain a desired and durable effect in vivo. We therefore propose that drug-target RT should be taken into account as an additional parameter in the lead selection and optimization process. This should ultimately lead to an increased number of candidate drugs moving to the preclinical development phase and on to the market. This review contains examples of the kinetics behavior of GPCR ligands with improved in vivo efficacy and summarizes methods for assessing drug-target RT.
大量已上市的药物作用于 G 蛋白偶联受体（GPCR），这是迄今为止最成功的药物靶点类别。这些药物通常具有高靶亲和力和选择性，这些综合特征一直是药物发现早期阶段的驱动力。然而，淘汰率也很高。由于缺乏疗效，许多新的研究性药物最终在临床试验中失败。对成功上市药物的回顾性评估表明，它们对患者的有益作用可能归因于它们与药物靶标的较长停留时间（RT）。同样，对于一些其他的 GPCR 药物，较短的 RT 可能有利于减少潜在的靶副作用。因此，化合物的动力学行为实际上可能是在体内获得所需和持久效果的指导原则。因此，我们建议将药物-靶标 RT 作为先导化合物选择和优化过程中的附加参数来考虑。这最终将导致更多的候选药物进入临床前开发阶段并推向市场。本文包含了一些具有改善体内疗效的 GPCR 配体的动力学行为的例子，并总结了评估药物-靶标 RT 的方法。
