4-substituted-5-acetyl-2-methyl-6-phenyl-3(2H)pyridazinones as PGE2 and IL-1 release inhibitors from mouse adherent macrophages.
A series of 4,5-functionalized 3(2H)-pyridazinones were evaluated as prostaglandin E2 (PGE2) and interleukin-1 (IL-1) release inhibitors from mouse adherent macrophages. Among the tested compounds only 2b was found to be devoid of activity in both the PGE2 and IL-1 tests, whereas the other compounds, showed a significant dose-dependent activity. Compounds 2a, 3 and 4 were able to inhibit PGE2 better than IL-1 release from stimulated macrophages. Compound 4, which showed an IC50 = 5.5 microM in the IL-1 test, appears to be a promising agent in this cell inflammation model. Structure-activity relationship (SAR) studies demonstrated the importance of the presence of a substituent characterized by a positive sigma constant at position 4 of the pyridazine system.
Dal Piaz
V
V
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Italy.
Giovannoni
M P
MP
Ciciani
G
G
Becherucci
C
C
Parente
L
L
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011724:Pyridazines / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007375:Interleukin-1; D011724:Pyridazines; D015232:Dinoprostone