Compound Aggregation in Drug Discovery: Implementing a Practical NMR Assay for Medicinal Chemists

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• 作者：Steven R. LaPlante ; Rebekah Carson ; James Gillard ; Norman Aubry ; Ren茅 Coulombe ; Sylvain Bordeleau ; Pierre Bonneau ; Michael Little ; Jeff O鈥橫eara ; Pierre L. Beaulieu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 27, 2013
• 年：2013
• 卷：56
• 期：12
• 页码：5142-5150
• 全文大小：626K
• 年卷期：v.56,no.12(June 27, 2013)
• ISSN：1520-4804

文摘

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 ¹H 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.