Solid-phase synthesis and inhibitory effects of some pyrido[1,2-c]pyrimidine derivatives on leukocyte functions and experimental inflammation

A number of pyrido[1,2-c]pyrimidines bearing a nitrogen, oxygen, or sulfur functionality at C-l were synthesized on solid-phase using the iminophospho rane methodology and tested for their effects on leukocyte functions in vit ro and antiinflammatory activity. Compound 5c was found to be a strong scav enger 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 nna crophages stimulated with lipopolysaccharide. Compounds 7, 5f, 6, and 8 inh ibited enzyme activity, whereas the remaining compounds also acted on the i nduction 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 edem a model, where they inhibited PGE(2) levels in inflamed paws without affect ing the content of this eicosanoid in stomachs. Inhibition of PGE2 producti on and superoxide scavenging may participate in the mechanism of the antiin flammatory action of these pyrido[1,2-c]pyrimidine derivatives.