Rácz Anita, Mihalovits Levente M, Beckers Maximilian, Fechner Nikolas, Stiefl Nikolaus, Sirockin Finton, McCoull William, Evertsson Emma, Lemurell Malin, Makara Gergely, Keserű György M
National Drug Research and Development Laboratory, Drug Innovation Centre, Research Centre for Natural Sciences, Budapest, Hungary.
Head Office, Chemaxon Ltd., Budapest, Hungary.
Nat Rev Drug Discov. 2025 Jul 7. doi: 10.1038/s41573-025-01225-1.
The goal of a small-molecule drug discovery campaign is the development of chemical entities that fulfil the criteria of the target product profile for progression into clinical trials. This objective is realized through multiparameter medicinal chemistry optimization, typically by identifying the compounds at the hit stage with molecular properties that provide a high chance of subsequent success, and then iteratively optimizing the properties, often in parallel, to identify leads and, ultimately, drug candidates. To assess the impact of medicinal chemistry optimizations on molecular properties, a set of new drug candidates reported in the literature between 2015 and 2022, and their corresponding hit and lead compounds, were analysed, and compared with a set of drug candidates identified between 2000 and 2010, and their corresponding hits and leads. This analysis was complemented by similar analyses of the internal medicinal chemistry programmes pursued at AstraZeneca and Novartis. Here, we highlight and discuss the implications of the observed trends, which include shifts in key physicochemical properties and strategic changes in medicinal chemistry programmes.
小分子药物研发活动的目标是开发出符合目标产品概况标准的化学实体，以便进入临床试验阶段。这一目标是通过多参数药物化学优化来实现的，通常是在命中阶段识别出具有较高后续成功可能性分子特性的化合物，然后迭代优化这些特性（通常是并行进行），以识别先导化合物，并最终确定候选药物。为了评估药物化学优化对分子特性的影响，我们分析了2015年至2022年间文献报道的一组新候选药物及其相应的命中化合物和先导化合物，并将其与2000年至2010年间确定的一组候选药物及其相应的命中化合物和先导化合物进行了比较。阿斯利康和诺华内部药物化学项目的类似分析对这一分析起到了补充作用。在此，我们突出并讨论了观察到的趋势的影响，这些趋势包括关键物理化学性质的变化以及药物化学项目的战略变化。
