Antiinflammatory activity of a series of substituted 2,3-dihydro-6-hydroxypyrimido[2,1-f]purine-4,8(1H,9H)-diones.
A series of substituted analogues based on the novel 2,3-dihydro-6-hydroxypyrimido[2,1-f]purine-4,8(1H,9H)-dione ring system have been synthesized and shown to exhibit antiinflammatory activity in the adjuvant-induced arthritis rat model (AAR). The activity exhibited by the pyrimidopurinediones in this model of chronic inflammation is comparable to that of their previously studied 2-oxo congeners, the 6-hydroxypyrimido[2,1-f]purine-2,4,8-(1H,3H,9H)-triones, the best of which show potency levels approximately equal to that of naproxen. On the basis of its potency in the AAR assay, 9-benzyl-2,3-dihydro-1,3-dimethyl-6-hydroxy-7-(3-methyl-2-butenyl) pyrimido-[2,1-f]purine-4,8(1H,9H)-dione was selected for further evaluation and found to exhibit cyclooxygenase inhibitory activity in the in vitro rat neutrophil model. With respect to side-effect liability, this prenylated derivative has been shown to be devoid of gastric ulcer inducing potential, as well as the ocular toxicity observed previously with the 2-oxo series.
Kaminski
J J
JJ
Pharmaceutical Research Division, Schering-Plough Corporation, Bloomfield, New Jersey 07003.
Solomon
D M
DM
Conn
D J
DJ
Wong
S C
SC
Chiu
P J
PJ
Massa
T
T
Siegel
M I
MI
Watnick
A S
AS
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D016861:Cyclooxygenase Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D010726:Phosphodiesterase Inhibitors