Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase

Members of three classes of pyridinylimidazoles bind with varying affinities to CSBP (p38) kinase which is a member of a stress-induced signal transduction pathway. Based upon SAR and protein homology modeling, the pharmacophore and three potential modes of binding to the enzyme are presented. For a subset of pyridinylimidazoles, binding is shown to correlate with inhibition of CSBP kinase activity, whereas no significant inhibition of PKA, PKCα and ERK kinase activity is observed. Members of the three classes of pyridinylimidazoles are shown to bind to CSBP (p38). A subset of these compounds is evaluated for CSBP, ERK, PKA and PKCα activity. A pharmacophore and potential modes of binding for the pyridinylimidazoles to CSBP are presented. [Display omitted]