Metabolite Identification via LC-SPE-NMR-MS of the In vitro Biooxidation Products of a Lead mGlu5 Allosteric Antagonist and Impact on the Improvement of Metabolic Stability in the Series
| Autor: | Martin Binder, Will Spooren, Simona M. Ceccarelli, Patrick Boissin, Steven P. Hanlon, Ernst Kupfer, Eric Prinssen, Andreas Stämpfli, Georg Jaeschke, Bernd Buettelmann, Iris Ruf, Jens-Uwe Peters, Eric Vieira, Sabine Kolczewski, Marianne Rueher, Porter Richard Hugh Phillip, Götz Schlotterbeck |
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| Rok vydání: | 2008 |
| Předmět: |
Magnetic Resonance Spectroscopy
Receptor Metabotropic Glutamate 5 Metabolite Allosteric regulation Aminopyridines Receptors Metabotropic Glutamate Mass spectrometry Biochemistry High-performance liquid chromatography Mass Spectrometry Inhibitory Concentration 50 chemistry.chemical_compound Allosteric Regulation Biotransformation Amide Drug Discovery Humans General Pharmacology Toxicology and Pharmaceutics Chromatography High Pressure Liquid Pharmacology Chromatography Metabotropic glutamate receptor 5 Solid Phase Extraction Organic Chemistry Stereoisomerism Metabolism Thiazoles Pharmaceutical Preparations chemistry Microsomes Liver Molecular Medicine Oxidation-Reduction |
| Zdroj: | ChemMedChem. 3:136-144 |
| ISSN: | 1860-7187 1860-7179 |
| DOI: | 10.1002/cmdc.200700203 |
| Popis: | Detailed information on the metabolic fate of lead compounds can be a powerful tool for an informed approach to the stabilization of metabolically labile compounds in the lead optimization phase. The combination of high performance liquid chromatography (HPLC) with nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) has been used to give comprehensive structural data on metabolites of novel drugs in development. Recently, increased automation and the embedding of on-line solid-phase extraction (SPE) into a integrated LC-SPE-NMR-MS system have improved enormously the detection limits of this approach. The new technology platform allows the analysis of complex mixtures from microsome incubations, combining low material requirements with relatively high throughput. Such characteristics make it possible to thoroughly characterize metabolites of selected compounds at earlier phases along the path to lead identification and clinical candidate selection, thus providing outstanding guidance in the process of eliminating undesired metabolism and detecting active or potentially toxic metabolites. Such an approach was applied at the lead identification stage of a backup program on metabotropic glutamate receptor 5 (mGlu5) allosteric inhibition. The major metabolites of a lead 5-aminothiazole-4-carboxylic acid amide 1 were synthesized and screened, revealing significant in vitro activity and possible involvement in the overall pharmacodynamic behavior of 1. The information collected on the metabolism of the highly active compound 1 was pivotal to the synthesis of related compounds with improved microsomal stability. |
| Databáze: | OpenAIRE |
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