Department of Chemistry, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard Street, Laval, Quebec H7S2G5, Canada.
J Med Chem. 2013 Jun 27;56(12):5142-50. doi: 10.1021/jm400535b. Epub 2013 Jun 13.
The pharmaceutical industry has recognized that many drug-like molecules can self-aggregate in aqueous media and have physicochemical properties that skew experimental results and decisions. Herein, we introduce the use of a simple NMR strategy for detecting the formation of aggregates using dilution experiments that can be performed on equipment prevalent in most synthetic chemistry departments. We show that (1)H NMR resonances are sensitive to large molecular-size entities and to smaller multimers and mixtures of species. Practical details are provided for sample preparation and for determining the concentrations of single molecule, aggregate entities, and precipitate. The critical concentrations above which aggregation begins can be found and were corroborated by comparisons with light scattering techniques. Disaggregation can also be monitored using detergents. This NMR assay should serve as a practical and readily available tool for medicinal chemists to better characterize how their compounds behave in aqueous media and influence drug design decisions.
制药行业已经认识到，许多类似药物的分子在水介质中会自聚集，并具有改变实验结果和决策的物理化学性质。在此，我们介绍了一种简单的 NMR 策略，用于通过稀释实验检测聚集的形成，该实验可以在大多数合成化学部门中常见的设备上进行。我们表明，(1)H NMR 共振对大分子量实体以及较小的多聚体和混合物物种敏感。提供了有关样品制备以及确定单分子、聚集实体和沉淀浓度的实用细节。可以找到开始聚集的临界浓度，并通过与光散射技术的比较得到证实。还可以使用去污剂监测解聚集。该 NMR 测定法应成为药物化学家的实用且易于获得的工具，以更好地了解他们的化合物在水介质中的行为并影响药物设计决策。
