Evaluation and optimization of physicochemical and metabolic properties of compounds are a crucial component of the drug development process. Continuous access to this information during the design-make-test-analysis cycle enables identification of chemical entities with suitable properties for efficient project progression. In this study, we describe an integrated and automated assay panel (DMPK Wave 1) that informs weekly on lipophilicity, solubility, human plasma protein binding, and metabolic stability in rat hepatocytes and human liver microsomes. All assays are running in 96-well format with ultraperformance liquid chromatography–mass spectrometry (MS)/MS as read-out. A streamlined overall workflow has been developed by optimizing all parts of the process, including shipping of compounds between sites, use of fit-for-purpose equipment and information systems, and technology for compound requesting, data analysis, and reporting. As a result, lead times can be achieved that well match project demands across sites independently of where compounds are synthesized. This robust screening strategy is run on a weekly basis and enables optimization of structure-activity relationships in parallel with DMPK properties to allow efficient and informed decision making.

中文翻译：

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用于早期药物代谢和药代动力学分析的完全集成的检测组。


化合物的理化和代谢特性的评估和优化是药物开发过程的重要组成部分。在设计-制造-测试分析周期中持续访问这些信息可以识别具有合适特性的化学实体，从而实现高效的项目进展。在这项研究中，我们描述了一个集成的自动化检测小组（DMPK Wave 1），每周提供有关大鼠肝细胞和人肝微粒体的亲脂性、溶解度、人血浆蛋白结合和代谢稳定性的信息。所有测定均以 96 孔格式运行，并以超高效液相色谱-质谱 (MS)/MS 读数。通过优化流程的所有部分，包括在站点之间运输化合物、使用适合用途的设备和信息系统以及化合物请求、数据分析和报告技术，开发了简化的整体工作流程。因此，无论化合物的合成地点如何，交货时间都可以很好地满足跨地点的项目需求。这种稳健的筛选策略每周运行一次，能够与 DMPK 特性并行优化结构-活性关系，从而实现高效、明智的决策。