title: 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.
authors.affiliation: Department of Chemistry, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard Street, Laval, Quebec H7S2G5, Canada. stevenrlaplante@gmail.com
authors.forename: Steven R
authors.initials: SR
authors.lastname: LaPlante
authors.forename: Rebekah
authors.initials: R
authors.lastname: Carson
authors.forename: James
authors.initials: J
authors.lastname: Gillard
authors.forename: Norman
authors.initials: N
authors.lastname: Aubry
authors.forename: René
authors.initials: R
authors.lastname: Coulombe
authors.forename: Sylvain
authors.initials: S
authors.lastname: Bordeleau
authors.forename: Pierre
authors.initials: P
authors.lastname: Bonneau
authors.forename: Michael
authors.initials: M
authors.lastname: Little
authors.forename: Jeff
authors.initials: J
authors.lastname: O'Meara
authors.forename: Pierre L
authors.initials: PL
authors.lastname: Beaulieu
mesh_terms: D003902:Detergents / Q000737:chemistry; D055808:Drug Discovery / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility
chemical_list: D003902:Detergents; D004364:Pharmaceutical Preparations