Chiral Sulfoxides as Metabolites of 2-Thioimidazole-Based p38α Mitogen-Activated Protein Kinase Inhibitors: Enantioselective Synthesis and Biological Evaluation
journal contributionposted on 12.05.2011, 00:00 by Stefanie Bühler, Marcia Goettert, Dieter Schollmeyer, Wolfgang Albrecht, Stefan A. Laufer
A number of pharmaceutically important drugs contain asymmetric sulfinyl moieties, so the biological evaluation of chiral sulfoxides as human drug metabolites is important for the development of safe and effective pharmaceuticals. Asymmetric oxidation is one of the most attractive ways to prepare chiral sulfoxides. In combination with different chiral ligands, the iron- and titanium-catalyzed asymmetric oxidations of tri- and tetrasubstituted 2-thioimidazoles afford the corresponding sulfoxides with enantiomeric excesses up to 99% as novel p38α mitogen-activated protein kinase (p38α MAPK) inhibitors. The enantiomerically pure sulfoxides were evaluated on their inhibitory potency against p38α MAPK compared to the respective sulfides and sulfoxide racemates and showed differences in their affinities for the enzyme with IC50 in the low nanomolar range. In addition, the ability to inhibit the release of tumor necrosis factor-α (TNF-α) from human whole blood (HWB) was examined. Some pyridinylimidazole derivatives showed excellent HWB activity with IC50 as low as 52 nM.