title: High throughput method for the indirect detection of intramolecular hydrogen bonding.
abstract: A supercritical fluid chromatography method was developed for the detection of intramolecular hydrogen bonds in pharmaceutically relevant molecules. The identification of compounds likely to form intramolecular hydrogen bonds is an important drug design consideration given the correlation of intramolecular hydrogen bonding with increased membrane permeability. The technique described here correlates chromatographic retention with the exposed polarity of a molecule. Molecules that can form an intramolecular hydrogen bond can hide their polarity and therefore exhibit lower retention than similar compounds that cannot. By use of a pairwise analysis strategy, intramolecular hydrogen bonds are identified within a test set of compounds with diverse topologies. The chromatographic results are confirmed by NMR chemical shift and temperature coefficient studies.
authors.affiliation: Groton Laboratories, Worldwide Medicinal Chemistry, Pfizer Global Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Gilles H
authors.initials: GH
authors.lastname: Goetz
authors.forename: William
authors.initials: W
authors.lastname: Farrell
authors.forename: Marina
authors.initials: M
authors.lastname: Shalaeva
authors.forename: Simone
authors.initials: S
authors.lastname: Sciabola
authors.forename: Dennis
authors.initials: D
authors.lastname: Anderson
authors.forename: Jiangli
authors.initials: J
authors.lastname: Yan
authors.forename: Laurence
authors.initials: L
authors.lastname: Philippe
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Shapiro
mesh_terms: D057166:High-Throughput Screening Assays; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D013058:Mass Spectrometry; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry*
chemical_list: D004364:Pharmaceutical Preparations