Pyridazines. Part XXIX: Synthesis and Platelet Aggregation Inhibition Activity of 5-Substituted-6-phenyl-3(2H)-pyridazinones. Novel Aspects of Their Biological Actions y Eddy Sotelo, a Nuria Fraiz, b Matilde Ya´n˜ez, b Vicente Terrades, a Reyes Laguna, b Ernesto Cano b and Enrique Ravin˜a a, * a Laboratorio de Quı´mica Farmace ´utica, Departamento de Quı´mica Orga ´nica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain b Departamento de Farmacologı´a, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain Received 26 February 2002; accepted 7 May 2002 Abstract—A series of 6-phenyl-3(2H)-pyridazinones with a diverse range of substituents in the 5-position have been prepared and evaluated in the search for new antiplatelet agents. A significant dependence of the substituent on the inhibitory effect has been observed. The pharmacological study of these compounds confirms that modification of the chemical group at position 5 of the 6- phenyl-3(2H)-pyridazinone system influences both variations in the antiplatelet activity and the mechanism of action. # 2002 Elsevier Science Ltd. All rights reserved. Under physiological conditions, the adhesion of plate- lets to the subendothelium of damaged vessel walls and subsequent platelet aggregation are critical events in haemostasis. 2,3 Nevertheless, the uncontrolled deposi- tion of platelets on the thrombogenic surface, such as ruptured atherosclerotic plaques, followed by formation of larger aggregates are the key steps in the development of various acute vasoocclusive diseases including unstable angina, myocardial infarction, transient ischemic attacks, stroke or reocclusion following thrombolytic therapy or angioplasty. 4 Aspirin, the primary antiplatelet therapy in use today, has been shown to reduce the risk of arterial thrombosis in placebo-controlled clinical trials. Despite the proven efficacy of aspirin, there are reasons to believe that sub- stantial improvements in antiplatelet therapy can be made. Among these is the fact that aspirin and the other currently available orally administered antiplatelet agents, such as ticlopidine and clopidogrel, are selective platelet inhibitors, and thus inhibit some but not all agonist-induced pathways of platelet activation and recruitment. Indeed, up to one third of patients respond in a limited manner to aspirin therapy, as determined by circulating platelet aggregate assay. 5 Several of the reasons discussed above have driven the search for new compounds that act on a common feature of platelet aggregation induced by different agonists, such as the platelet fibrinogen receptor antagonists that have become a target in the search for more efficient antiplatelet drugs. 6 Despite extensive research in the area of GP IIb/IIIa inhibitors, only limited progress has been made in the search for orally active anti-thrombotic drugs and, recently, several bleeding complications have been reported during the use of these compounds in clinical trials. 7 Thus, new agents having a broad mechanism of action are of great inter- est not only for use as drugs but also because they are pharmacological tools that provide important informa- tion about platelet function. In recent years, the 6-phenyl-3(2H)-pyridazinone system has aroused a great deal of attention due to its struc- tural relationship to the 5-aryl-2(1H)-pyridones and, in particular, to milrinone and amrinone, the prototypes of a series of non-glycoside, non-catecholamine-based 0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S0968-0896(02)00146-3 Bioorganic & Medicinal Chemistry 10 (2002) 2873–2882 y Part of this work was presented at the 7th International Symposium on the Chemistry and Pharmacology of Pyridazines, Santiago de Compostela, Spain, September, 2000. For the previous paper in this series, see ref 1. *Corresponding author. Tel.: +34-981-594628; fax: +34-981-594912; e-mail: qofara@usc.es