Assessing Physicochemical Properties of Drug Molecules via Microsolvation Measurements with Differential Mobility Spectrometry.

Autor:	Liu C; SCIEX , 71 Four Valley Drive, Concord, Ontario, L4K 4V8, Canada., Le Blanc JC; SCIEX , 71 Four Valley Drive, Concord, Ontario, L4K 4V8, Canada., Schneider BB; SCIEX , 71 Four Valley Drive, Concord, Ontario, L4K 4V8, Canada., Shields J; Pfizer Global Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States., Federico JJ 3rd; Pfizer Global Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States., Zhang H; Pfizer Global Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States., Stroh JG; Pfizer Global Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States., Kauffman GW; Pfizer Global Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States., Kung DW; Pfizer Global Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States., Ieritano C; Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada., Shepherdson E; Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada., Verbuyst M; Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada., Melo L; Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada., Hasan M; Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada., Naser D; Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada., Janiszewski JS; Pfizer Global Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States., Hopkins WS; Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada., Campbell JL; SCIEX, 71 Four Valley Drive, Concord, Ontario, L4K 4V8, Canada; Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.
Jazyk:	angličtina
Zdroj:	ACS central science [ACS Cent Sci] 2017 Feb 22; Vol. 3 (2), pp. 101-109. Date of Electronic Publication: 2017 Feb 10.
DOI:	10.1021/acscentsci.6b00297
Abstrakt:	The microsolvated state of a molecule, represented by its interactions with only a small number of solvent molecules, can play a key role in determining the observable bulk properties of the molecule. This is especially true in cases where strong local hydrogen bonding exists between the molecule and the solvent. One method that can probe the microsolvated states of charged molecules is differential mobility spectrometry (DMS), which rapidly interrogates an ion's transitions between a solvated and desolvated state in the gas phase (i.e., few solvent molecules present). However, can the results of DMS analyses of a class of molecules reveal information about the bulk physicochemical properties of those species? Our findings presented here show that DMS behaviors correlate strongly with the measured solution phase p K a and p K b values, and cell permeabilities of a set of structurally related drug molecules, even yielding high-resolution discrimination between isomeric forms of these drugs. This is due to DMS's ability to separate species based upon only subtle (yet predictable) changes in structure: the same subtle changes that can influence isomers' different bulk properties. Using 2-methylquinolin-8-ol as the core structure, we demonstrate how DMS shows promise for rapidly and sensitively probing the physicochemical properties of molecules, with particular attention paid to drug candidates at the early stage of drug development. This study serves as a foundation upon which future drug molecules of different structural classes could be examined.
Databáze:	MEDLINE
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