Tetrahydropyridine derivatives with inhibitory activity on the production of proinflammatory cytokines: Part 1

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 16, 2009, Pages 4607-4610

  Nakao, Akira ^a   Ohkawa, Nobuyuki ^a   Nagasaki, Takayoshi ^a   Kagari, Takashi ^a   Doi, Hiromi ^a   Shimozato, Takaichi ^a   Ushiyama, Shigeru ^a   Aoki, Kazumasa ^a  

^a DAIICHI SANKYO CO   (Japan)

Author keywords

Anti inflammatory agent; p38 MAP kinase; Proinflammatory cytokine; TNF

Indexed keywords

4 (4 FLUOROPHENYL) 2 (4 METHYLSULFINYLPHENYL) 5 (4 PYRIDYL)IMIDAZOLE; LIPOPOLYSACCHARIDE; LYMPHOTOXIN; PYRIDINE DERIVATIVE; TUMOR NECROSIS FACTOR INHIBITOR;

ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; CYTOKINE PRODUCTION; DRUG ACTIVITY; DRUG SYNTHESIS; IC 50; MOUSE; NONHUMAN;

ANIMALS; ANTI-INFLAMMATORY AGENTS; HUMANS; IMIDAZOLES; LIPOPOLYSACCHARIDES; MICE; PYRIDINES; PYRROLES; TUMOR NECROSIS FACTOR-ALPHA;

MUS;

EID: 67651097818     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.06.094     Document Type: Article

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20. Fresh blood was collected aseptically in the presence of heparin by venipuncture from healthy adult volunteers. The subjects did not have any apparent inflammatory conditions and had taken no drug for at least 7 days prior to blood collection. Written informed consent was obtained from all volunteers before the experiments. Blood aliquots of 988 μL were mixed with either 2 μL of a test compound solution or 2 μL of DMSO, and with 10 μL of 1.0 mg/mL LPS (dissolved in PBS, final concentration: 10 μg/mL) in Eppendorf tubes. The compounds were dissolved and diluted to the appropriate concentrations with DMSO. The compound solutions were prepared immediately before use. The mixture was incubated at 37 °C for 6 h. Control assays were carried out in additional tubes by mixing blood with 2 μL of DMSO and 10 μL of PBS instead of the test compounds and LPS (negative control), respectively. After the incubation was finished, the mixture was immediately chilled at 4 °C and centrifuged at 15,300g for 5 min, and the plasma was stored at -20 °C until the assay. The levels of cytokines in the plasma were determined by using commercially available immunoassay kits. The percent inhibition of cytokine production by the compounds was calculated by the following equation: Percent inhibition of cytokine production = {1 - (concentration of cytokine in the reaction mixture of test compound - concentration of cytokine in the reaction mixture of negative control)/(concentration of cytokine in the reaction mixture of control - concentration of cytokine in the reaction mixture of the negative control)} × 100.
21. We tried to synthesize an analogue possessing an aminoethyl group (n = 2), but it was too unstable a compound to isolate.
22. TNFα production was induced in mice by the procedure of Griswold et al. (J. Immunol. Methods 1996, 195, 1-5.) with a slight modification. In brief, mice were deprived of food overnight, but not water. The next day, these mice were orally administered with test compounds suspended in 0.5% CMC aqueous solution at 10 mL/kg except normal and control mice that were administered with 0.5% CMC aqueous solution. Thirty minutes later, LPS solution dissolved in physiological saline was intravenously injected at 0.45-mg/10 mL/kg except for the normal mice, which were injected with physiological saline at 10 mL/kg. One hour later, blood samples were taken from the mice from the vena cava inferior into a syringe containing heparin sodium. After centrifugation of the blood samples at 13,230g for 3 min at 4 °C, plasma samples were taken immediately and frozen at -20 °C until measurement of the concentration of TNFα in the plasma sample. The concentrations of TNFα in the plasma samples were measured with commercially available ELISA kits. The percent inhibition of TNFα production was obtained by the following equation: Percent inhibition = {1 - (concentration of TNFα in plasma sample of mice administrated test compounds - mean concentration of TNFα in the plasma samples of normal mice)/(concentration of TNFα in the plasma samples in control mice - mean concentration of TNFα in the plasma samples of normal mice)} × 100.