title: Chiral sulfoxides as metabolites of 2-thioimidazole-based p38α mitogen-activated protein kinase inhibitors: enantioselective synthesis and biological evaluation.
abstract: 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 IC(50) 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 IC(50) as low as 52 nM.
authors: Department of Pharmaceutical/Medicinal Chemistry, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors: Stefanie
authors: S
authors: Bühler
authors: Marcia
authors: M
authors: Goettert
authors: Dieter
authors: D
authors: Schollmeyer
authors: Wolfgang
authors: W
authors: Albrecht
authors: Stefan A
authors: SA
authors: Laufer
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000097:blood; D015394:Molecular Structure; D013237:Stereoisomerism; D013454:Sulfoxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007093:Imidazoles; D013454:Sulfoxides; D014409:Tumor Necrosis Factor-alpha; D048308:Mitogen-Activated Protein Kinase 14