5-Acyl-6-aryl-4-nitro-3(2H)pyridazinones and related 4-amino compounds: synthesis and pharmacological evaluation

• Published in: Journal of pharmaceutical sciences Vol. 80; no. 4; p. 341
• Main Authors: Dal Piaz, V, Ciciani, G, Turco, G, Giovannoni, M P, Miceli, M, Pirisino, R, Perretti, M
• Format: Journal Article
• Language: English
• Published: United States 01.04.1991
• Subjects: Amrinone - analogs & derivatives; Amrinone - chemical synthesis; Amrinone - pharmacology; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Humans; In Vitro Techniques; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Platelet Aggregation Inhibitors - chemical synthesis; Pyridazines - chemical synthesis; Pyridazines - pharmacology; Rabbits; Rats; Rats, Inbred Strains
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.2600800412

Several 4-nitro- and 4-amino-5-acyl-6-aryl-3(2H)pyridazinones were prepared and their in vitro and ex vivo antiaggregatory properties were evaluated. 4-Nitro derivatives 3 generally showed good activity in vitro towards arachidonic acid (AA)-induced human blood platelet aggregation. The 4-amino compound 4a, which has weak in vitro activity, exhibited antiplatelet activity, particularly on adenosine dephosphate (ADP)-induced aggregation ex vivo in rabbit. Moreover, the same compound was shown to be active in platelet-activating factors (PAF)-induced rat paw hyperalgesia and to be endowed with low acute oral toxicity. The 4-amino derivatives 4a-m and the other pyridazinones 5-9 administered orally to rats were also found to be more potent antiinflammatory agents than acetyl salicylic acid (ASA). Compounds 3a and 4a, tested in vitro on lipopolysaccharide (LPS)-stimulated rat peritoneal macrophages, were seen to be active in the inhibition of prostaglandin E2 (PGE2) production and interleukin-1 activity. Structure-activity relationship studies in the series of antiaggregating pyridazinones 3 have shown the primary importance of the nitro and acetyl substituents at positions 4 and 5, respectively. Hydrophobic substituents at position 2 were also required for better activity.