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Compound aggregation in drug discovery: implementing a practical NMR assay for medicinal chemists.

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

LaPlante SR,Carson R,Gillard J,Aubry N,Coulombe R,Bordeleau S,Bonneau P,Little M,O'Meara J,Beaulieu PL

doi

10.1021/jm400535b

subject

Has Abstract

pub_date

2013-06-27 00:00:00

pages

5142-50

issue

12

eissn

0022-2623

issn

1520-4804

journal_volume

56

pub_type

杂志文章

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