Synthesis and study of the anti-inflammatory properties of some pyrazolo[1,5-a]pyrimidine derivatives.
A series of pyrazolo[1,5-a]pyrimidin-7-ones (1c-17c) were synthesized to evaluate in vivo and in vitro effects induced by structural modifications at the 2 position of 4,7-dihydro-4-ethyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-one (FPP028). This substance, which has been previously studied, is a weak inhibitor of prostaglandin biosynthesis and a nonacid analgesic and anti-inflammatory agent devoid of ulcerogenic properties. To gain more insight into the mechanism of action of this class of compounds, several in vivo tests were carried out, such as carrageenan-induced rat paw edema and pleurisy. In vitro tests include some studies of leukocyte functions, such as superoxide production and myeloperoxidase release. In vitro effects on arachidonic acid-, adenosine 5'-diphosphate-, and platelet-activating factor-induced platelet aggregation were also studied. Different anti-inflammatory activities were observed, depending on the nature of substituents at the 2 position; these differences are probably linked to the capacity of these compounds to inhibit leukotrienes and/or prostaglandin biosynthesis with different selectivity. 4,7-Dihydro-4-ethyl-2(2-thienyl)pyrazolo[1,5-a]pyrimidin-7-one (7c) proved to be the most interesting compound of the novel synthesized series, showing powerful pharmacological activity in vivo as well as in vitro, together with very weak acute toxicity.
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Italy.
F
F
Bruni
A
A
Costanzo
S
S
Selleri
G
G
Guerrini
R
R
Fantozzi
R
R
Pirisino
S
S
Brunelleschi
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001792:Blood Platelets / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D010998:Pleurisy / Q000139:chemically induced / Q000517:prevention & control; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D013929:Thromboxane B2 / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D013481:Superoxides; D007975:Leukotriene B4; D013929:Thromboxane B2; D009195:Peroxidase