An in-vitro screening assay for the detection of inhibitors of proinflammatory cytokine synthesis: a useful tool for the development of new antiarthritic and disease modifying drugs

Q2 · MEDICINE

Article

Author: T. Bertsche ; S. Laufer ; C. Greim

OBJECTIVEThis work targets the development of a new tool to help develop new anticytokine drugs that prevent or reduce the progression of arthritic diseases. The specific aim of our study was to establish a fast and reliable in vitro screening assay of cytokine synthesis inhibitors (TNFalpha, IL-1beta) which shows better correlation with enzyme assays than previously reported in vitro assays. The test system should be able to detect p38-MAP kinase inhibitors.MATERIAL AND METHODSHuman peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll density gradient centrifugation from human EDTA-potassium whole blood. Cells were adjusted at 1 x 10(6) cells/ml. PBMCs were stimulated with lipopolysaccharide (LPS; E. coli serotype 026:B6: 1 microg/ml) in the presence of test compound (10(-5)-10(-8)M) for 4h at 37 degrees C in a 5% CO(2)-incubator. Induced TNFalpha and IL-1beta protein were measured by ELISA.RESULTSThe following are representative examples of inhibitors which effect cytokine synthesis. Corticoid Dexamethasone inhibits IL-1beta and TNFalpha synthesis at IC(50) of 38 nM and 25 nM, respectively. ERK1/ERK2 inhibitor U0126 effects cytokine synthesis at IC(50) of 0.34 microM for IL-1beta production and 0.26 microM for TNFalpha synthesis.p38-MAP kinase inhibitor SB 203580 inhibits IL-1beta- and TNF-alpha-synthesis (IC(50)sof 0.052 microM and 0.46 microM) in the same degree as p38-MAP kinase activity (IC(50): 0.34 microM). Same results could be shown for SB 210313, which had same efficacy on IL-1beta and TNFalpha biosynthesis (IC(50)'s: 1.88 microM and 1.01 microM) and on p38-MAP kinase (IC(50): 6.85 microM). Also for SB 202190 this correlation in inhibition of IL-1beta and TNFalpha synthesis (IC(50)'s: 0.055 microM and 1.01 microM) and p38-MAP kinase inhibition (IC(50): 0.088 microM) could be shown.CONCLUSIONThis study shows the screening assay using PBMCs stimulated with LPS for IL-1beta and TNFalpha synthesis is a reliable test system for the quantification of the effectiveness of new drugs modulating IL-1beta and TNFalpha synthesis which is mainly mediated by p38-MAP Kinase. These assay allows fast detection of IL-1beta and TNFalpha synthesis inhibitors with different modes of action, including p38-MAP kinase inhibitors. The results obtained with our in-vitro screening assay show good correlation with results from enzyme assays.

01 Oct 2002·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

Design, synthesis and bioactivities of novel diarylthiophenes: inhibitors of tumor necrosis factor-α (TNF-α) production

Q3 · MEDICINE

Article

Author: Tetsuya Hirayama ; Masakazu Fujita ; Naoko Ikeda

The design, synthesis and SAR of novel diarylthiophene derivatives were performed. These compounds were designed by structural hybridization of TNF-alpha production inhibitors bearing 4-fluorophenyl and 4-pyridyl groups such as FR133605, FR167653 and SB210313, and 6-acetyl-3-ethoxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (1) found previously by us. As a result, several compounds were more potent in vitro than FR133605 against TNF-alpha production stimulated with lipopolysaccharide (LPS).

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Indication	Highest Phase	Country/Location	Organization	Date
Rheumatoid Arthritis	Preclinical	GB	Smithkline Beecham Pharmaceuticals (India) Ltd.	-

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