title: Antiinflammatory activity of a series of substituted 2,3-dihydro-6-hydroxypyrimido[2,1-f]purine-4,8(1H,9H)-diones.
abstract: 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.
authors.affiliation: Pharmaceutical Research Division, Schering-Plough Corporation, Bloomfield, New Jersey 07003.
authors.forename: J J
authors.initials: JJ
authors.lastname: Kaminski
authors.forename: D M
authors.initials: DM
authors.lastname: Solomon
authors.forename: D J
authors.initials: DJ
authors.lastname: Conn
authors.forename: S C
authors.initials: SC
authors.lastname: Wong
authors.forename: P J
authors.initials: PJ
authors.lastname: Chiu
authors.forename: T
authors.initials: T
authors.lastname: Massa
authors.forename: M I
authors.initials: MI
authors.lastname: Siegel
authors.forename: A S
authors.initials: AS
authors.lastname: Watnick
mesh_terms: 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
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D010726:Phosphodiesterase Inhibitors