Pharmacological activity of some pyrrolo and pyrazolo pyrimidine derivatives.
4,7-Dihydro-4-ethyl-2-phenylpyrazolo-[1,5-a]pyrimidin-7-one (FPP028) is the prototype of a class of pyrazolo[1,5-a]pirimidine derivatives that has been shown to possess marked antiinflammatory and analgesic properties; 1,4-dihydro-1-ethyl-7-phenylpyrrolo[1,2-a]pyrimidin-4-one (FPP129) is a new compound belonging to a series of pyrrolo[1,2-a]pirimidine derivatives that has been synthetized in an attempt to reduce certain toxic effects observed with FPP028. To evaluate these two compounds more fully, in the present study we determined the LD50 of FPP129 in mice and assessed its activity in different experimental inflammation models. Ulcerogenic properties of FPP129 were evaluated by the test of stress-induced ulcer in rats. We also studied the in vitro and ex vivo effects of both FPP028 and FPP129 in a series of platelet-aggregation experiments using either arachidonate or collagen as aggregating agents. In the carraggeenan-induced paw edema, FPP129 exerted a marked anti-inflammatory activity with an ED50 of 22.2 mg/kg. FPP129 inhibited also the edema induced by concanavalin-A or Paf-acether. The in vitro anti-aggregatory activity of FPP028 was shown to be much less than that of indomethacin, thus confirming the hypothesis that the compound is a very weak inhibitor of cyclooxygenase. Ex vivo, both FPP028 and FPP129 were shown to exert no antiaggregatory effect in rabbits after administration of doses equal to the ED50. No ulcerogenic activity was found with FPP129, this result being consistent with previous observations on FPP028. Our data show tha FPP028 and FPP129 do not share a typical mechanism of action (cyclooxygenase inhibition) found with the majority of nonsteroidal antiinflammatory drugs. Nonetheless, the antiinflammatory properties of these compounds, together with their lack of ulcerogenic activity, indicate that both FPP028 and FPP129 are potentially interesting for future therapeutic use.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002351:Carrageenan; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007928:Lethal Dose 50; D008297:Male; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles / Q000494:pharmacology* / Q000633:toxicity; D011743:Pyrimidines / Q000494:pharmacology* / Q000633:toxicity; D011758:Pyrroles / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D012149:Restraint, Physical; D013276:Stomach Ulcer / Q000139:chemically induced
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011758:Pyrroles; D002351:Carrageenan; D007213:Indomethacin