On the basis of model imidazole inhibitors of cytokine release, a series of novel pyridinyl pyrimidine derivatives was prepared and tested on their ability to inhibit the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) from peripheral blood mononuclear cells (PBMC) and human whole blood. In the pyrimidine series, structure-activity relationships (SARs) similar to those of the imidazole series were found, although generally pyrimidine compounds were less potent. Modification of the substituent at the 2 position of the pyrimidine led to the most active compound 14 which inhibited release of TNF-alpha (IC(50) = 3.2 microM) and IL-1beta (IC(50) = 2.3 microM) from PBMC as effectively as the model imidazole inhibitor ML 3163 (TNF-alpha, IC(50) = 3.7 microM; IL-1beta, IC(50) = 0.9 microM). Screening in an isolated enzyme assay revealed both imidazole and pyrimidine compounds as inhibitors of p38 MAP (mitogen-activated protein) kinase.