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).