title: Ratio encoding combinatorial libraries with stable isotopes and their utility in pharmaceutical research.
abstract: Combinatorial libraries are an important tool for lead discovery in the pharmaceutical industry. Advances in high throughput screening coupled with combinatorial chemistry can significantly reduce the time to find lead compounds. A major difficulty in developing large combinatorial libraries is the ability to identify active compounds. This paper describes a rapid and sensitive encoding/decoding methodology that utilizes stable isotopes and mass spectrometry. The ability of mass spectrometry to precisely determine the intensity of isotopic abundances provides a unique encoding strategy employing synthetically generated ratios of stable isotopes in a compound as the code. The application of ratio encoding is demonstrated using peptoid and imidazole chemistries. Supporting data demonstrate that the incorporation of one or more stable isotopes using unique-predetermined ratios can encode chemical libraries. In addition, the presence of a unique isotopic pattern in a ligand can facilitate the pharmacokinetic analysis. Isotope incorporation into a compound and subsequently into its metabolites reliably distinguishes products from other molecules in the mass spectrum. This is illustrated by metabolic analyses of peptoid and imidazole compounds.
authors.affiliation: GlaxoWellcome Research Institute, Research Triangle Park, NC 27709, USA. DSW23183@glaxowellcome.com
authors.forename: D S
authors.initials: DS
authors.lastname: Wagner
authors.forename: C J
authors.initials: CJ
authors.lastname: Markworth
authors.forename: C D
authors.initials: CD
authors.lastname: Wagner
authors.forename: F J
authors.initials: FJ
authors.lastname: Schoenen
authors.forename: C E
authors.initials: CE
authors.lastname: Rewerts
authors.forename: B K
authors.initials: BK
authors.lastname: Kay
authors.forename: H M
authors.initials: HM
authors.lastname: Geysen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004345:Drug Industry / Q000379:methods; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry; D007554:Isotopes / Q000032:analysis*; D013058:Mass Spectrometry / Q000379:methods*; D008862:Microsomes, Liver / Q000378:metabolism; D008969:Molecular Sequence Data; D009587:Nitrogen Isotopes; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D034444:Peptoids; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D012106:Research; D012984:Software; D018909:src Homology Domains
chemical_list: D007093:Imidazoles; D007554:Isotopes; D009587:Nitrogen Isotopes; D019151:Peptide Library; D010455:Peptides; D034444:Peptoids; D003577:Cytochrome P-450 Enzyme System; D016392:Proto-Oncogene Proteins pp60(c-src)