title: Synthesis and evaluation as platelet aggregation inhibitors of 6-phenyl-2,4-substituted-3(2H)-pyridazinones and their rigid analogues benzo[h]cinnolin-3,5-diones.
abstract: A series of 5-acyl-6-phenyl-2,4-substituted-3(2H)-pyridazinones and analogous benzo[h]cinnolin-3,5-diones with reduced flexibility has been prepared and evaluated as human platelet aggregation inhibitors. The 4-methylsulfoxide 13b was the most potent compound of the series (IC50 = 1.2 microM). SAR studies have shown the primary importance of an electronegative substituent at position 4 and an acetyl group at position 5 of the pyridazine system for potent platelet aggregation inhibitory activity. Biological tests performed on a group of representative compounds showed these products have not effects on prostaglandins, thromboxanes and nitric oxide biosynthetic pathways. Some of synthesized compounds produced a moderate increase of cAMP level in platets which does not depend on the adenylate-cyclase stimulation. Tests performed on human platelet PDE III have shown that these compounds are not inhibitors of this enzyme.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Firenze, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Dal Piaz
authors.forename: G
authors.initials: G
authors.lastname: Ciciani
authors.forename: M P
authors.initials: MP
authors.lastname: Giovannoni
mesh_terms: D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D010975:Platelet Aggregation Inhibitors; D011724:Pyridazines