5-Acyl-6-aryl-4-nitro-3(2H)pyridazinones and related 4-amino compounds: synthesis and pharmacological evaluation.
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.
Dal Piaz
V
V
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Italy.
Ciciani
G
G
Turco
G
G
Giovannoni
M P
MP
Miceli
M
M
Pirisino
R
R
Perretti
M
M
D000676:Amrinone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis; D006801:Humans; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010975:Platelet Aggregation Inhibitors; D011724:Pyridazines; D000676:Amrinone