Unexpected reaction of 2-alkylsulfanylimidazoles to imidazol-2-ones: pyridinylimidazol-2-ones as novel potent p38alpha mitogen-activated protein kinase inhibitors.
While optimizing the synthesis of 2-alkylsulfanyl-5-(2-aminopyridin-4-yl)imidazoles, we identified an unexpected reaction to pyridinylimidazol-2-ones. 2-Alkylsulfanylimidazoles, bearing a 2-hydroxyethyl or a 2,3-dihydroxypropyl moiety at the imidazole C2-S position, were converted by heating into imidazol-2-ones. These imidazol-2-ones were tested for their ability to inhibit p38alpha MAP kinase and LPS-stimulated TNF-alpha release in HWB. Introduction of an amino moiety at the pyridine C2 position led to compounds showing potent enzyme inhibitory activity with double-digit nanomolar IC(50) values (5a: IC(50) = 23 nM).
Koch
Pierre
P
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard Karls University of Tubingen, Auf der Morgenstelle 8, 72076 Tubingen, Germany.
Laufer
Stefan
S
D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D007093:Imidazoles; D008070:Lipopolysaccharides; D011725:Pyridines; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha; D048308:Mitogen-Activated Protein Kinase 14