Early prediction of elimination pathways for new chemical entities can have a profound impact on drug discovery programs. The recently proposed Extended Clearance Classification System (ECCS) is a step in the right direction, providing a framework to help identify the major elimination pathway of a drug. A list of 42 Amgen small molecules was evaluated against the ECCS framework to assess its performance in retrospectively predicting their major elimination pathway. Here, we present a critical analysis of the chemical space defined by the ECCS framework with the aim of identifying its applicability and constraints. This evaluation highlights the critical need for periodic review and revision of ECCS, given that target constraints are moving molecules away from the traditional ‘drug-like’ physicochemical space.

新化学实体消除途径的早期预测可以对药物发现计划产生深远的影响。最近提出的扩展清除分类系统 (ECCS) 是朝着正确方向迈出的一步，它提供了一个框架来帮助确定药物的主要消除途径。针对 ECCS 框架评估了 42 种 Amgen 小分子的列表，以评估其在回顾性预测其主要消除途径方面的性能。在这里，我们对 ECCS 框架定义的化学空间进行了批判性分析，目的是确定其适用性和约束条件。鉴于目标限制正在使分子远离传统的“类药物”物理化学空间，因此该评估强调了对 ECCS 进行定期审查和修订的迫切需要。