From Imidazoles to Pyrimidines:  New Inhibitors of Cytokine Release

Abstract

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.

Intracellular Delivery of the p38 Mitogen-Activated Protein Kinase Inhibitor SB202190 [4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole] in Renal Tubular Cells: A Novel Strategy to Treat Renal Fibrosis

“…Our new linkage technology ULS produced drug-LZM conjugates that display a sustained release of the drug in tubular cells for several days, which is an advantageous characteristic for drugs against chronic diseases. In addition, a large number of drugs containing nitroaromatic rings such as pyridine, pyrimidine, or imidazole groups (English and Cobb, 2002;Laufer and Wagner, 2002) may be potential candidates for the ULS coupling approach.…”

Biological studies on Brazilian plants used in wound healing

“…Therefore, a "black box" like the human whole blood assay may be appropriate as it provides a summary result of various molecular actions. This assay was already successfully used to evaluate p38 MAPK inhibitors (Laufer et al, 2002a,b;Laufer and Wagner, 2002).…”

Synthesis, Biological Testing, and Binding Mode Prediction of 6,9-Diarylpurin-8-ones as p38 MAP Kinase Inhibitors

“…The first aryl, a 4-pyridyl moiety, mimics a conserved hydrogen bond, originally formed between N-1 of ATP and the backbone amide N-H of Met 109 (Figure 1). 5 The second aryl, a 4-fluorophenyl moiety occupies the kinase's hydrophobic region I which is pocket-shaped ( Figure 2). Intriguingly, ATP does not occupy this hydrophobic region I (selectivity pocket) when bound to the kinase (Figure 1), thus providing opportunities for the design of selective inhibitors with an appropriate substitution pattern targeting region I and, in order to increase affinity, region II.…”