Solid-phase synthesis and inhibitory effects of some pyrido[1,2-c]pyrimidine derivatives on leukocyte formations and experimental inflammation.
A number of pyrido[1,2-c]pyrimidines bearing a nitrogen, oxygen, or sulfur functionality at C-1 were synthesized on solid-phase using the iminophosphorane methodology and tested for their effects on leukocyte functions in vitro and antiinflammatory activity. Compound 5c was found to be a strong scavenger of superoxide anion and an inhibitor of chemiluminescence induced by 12-O-tetradecanoylphorbol 13-acetate in human neutrophils. These pyrido[1,2-c]pyrimidines inhibited the generation of PGE(2) by COX-2 in RAW 264.7 macrophages stimulated with lipopolysaccharide. Compounds 7, 5f, 6, and 8 inhibited enzyme activity, whereas the remaining compounds also acted on the induction phase. In addition, 5a-f, 6, and 7 administered p.o. at a dose of 20 mg/kg showed antiinflammatory activity in the carrageenan mouse paw edema model, where they inhibited PGE(2) levels in inflamed paws without affecting the content of this eicosanoid in stomachs. Inhibition of PGE(2) production and superoxide scavenging may participate in the mechanism of the antiinflammatory action of these pyrido[1,2-c]pyrimidine derivatives.
Molina
P
P
Departamento de Química Orgánica, Universidad de Murcia, Murcia E-30071, Spain. pmolina@um.es
Aller
E
E
Lorenzo
A
A
López-Cremades
P
P
Rioja
I
I
Ubeda
A
A
Terencio
M C
MC
Alcaraz
M J
MJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000037:antagonists & inhibitors; D004487:Edema / Q000188:drug therapy; D016166:Free Radical Scavengers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides; D008163:Luminescent Measurements; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D008565:Membrane Proteins; D051379:Mice; D018375:Neutrophil Activation; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D010196:Pancreatic Elastase / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016166:Free Radical Scavengers; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011743:Pyrimidines; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010196:Pancreatic Elastase; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate