Inhibition of iNOS and COX-2 in human whole blood ex vivo and monocyte-macrophage J774 cells by a new group of aminothiopyrimidone derivatives.
We tested a series of 11 new aminothiopyrimidones on the activity of inducible nitric oxide synthase (iNOS) and prostaglandin G/H synthase-1 and 2 (COX-1 and COX-2) in the whole human blood and monocyte-macrophage J774 cell line. To induce COX-2 and iNOS, blood samples and J774 cells were stimulated with bacterial lipopolysaccharide (LPS) in the absence or presence of the test compounds. After incubation, the plasma and the supernatants of culture media were collected for the measurement of TxB(2) and PGE(2) by a specific enzyme-immunoassay and determination of nitrite by a colorimetric assay. Several phenylthieno derivatives of substituted pyrimidone inhibited formation of both COX-2 and iNOS derived products with one of the compounds (compound 11, N-[2-[(2,4-dinitrophenyl)thio]-4-oxo-6-phenylthieno[2,3-d]pyrimidin-3(4H)-y]methanesulfonamide) showing a complete inhibition of LPS-stimulated formation of NO and PGE(2).
Cardile
Venera
V
Department of Physiological Sciences, University of Catania, Catania, Italy. cardile@unict.it
Lombardo
Laura
L
Granata
Giuseppe
G
Perdicaro
Antonio
A
Balazy
Michael
M
Santagati
Andrea
A
D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000097:blood* / Q000737:chemistry; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007962:Leukocytes / Q000201:enzymology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C540837:N-(2-((2,4-dinitrophenyl)thio)-4-oxo-6-phenylthieno(2,3-d)pyrimidin-3(4H)-y)methanesulfonamide; D011743:Pyrimidines; D011744:Pyrimidinones; D013449:Sulfonamides; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone