Pyridazines. Part 28: 5-Alkylidene-6-phenyl-3(2H)-pyridazinones, a New Family of Platelet Aggregation Inhibitors § Eddy Sotelo, a Nuria Fraiz, b Matilde Ya´n˜ez, b Reyes Laguna, b Ernesto Cano, b Jose´ Brea b and Enrique Ravin˜a a, * a Departamento de Quı´mica Orga ´nica, Laboratorio de Quı´mica Farmace ´utica, 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 12 December 2001; revised 4 March 2002; accepted 12 April 2002 Abstract—The synthesis and anti-platelet activity of several 5-alkylidene-6-phenyl-3(2H)-pyridazinones are described. The most active compounds are those that contain oxygenated functions (COOR, COMe) on the alkylidene fragment (6a, 6b and 6c). # 2002 Published by Elsevier Science Ltd. The activation, adhesion and aggregation of platelets are all important processes in the initiation of thrombus formation at sites showing high-grade stenosis, ruptured atheromatous plaque and endothelial damage within arteries. Platelet-mediated thrombus formation in the coronary artery is a primary factor in the development of thrombotic disorders such as unstable angina, myo- cardial infarction, stroke and peripheral artery dis- ease. 2,3 The medical need for more efficacious anti- platelet agents and the growing understanding of the role of platelets in vascular injury have catalysed an extensive evaluation of novel approaches to control platelet function. Current therapeutic-based strategies to inhibit platelet function include the use of Aspirin, Ticlopidine or Sul- finpyrazone (Fig. 1) but some of these drugs are not selective and have a relatively low activity. In the search for new, highly active and selective agents, the field of GP IIb-IIIa has been investigated and several drugs have been identified that have the fibrinogen receptor as a target. 4,5 Nevertheless, several complications involving bleeding have recently been described on using these drugs in clinical trials. 6 8 Thus, the search for new agents with other mechanisms of action is of great interest not only for use as drugs but also because such compounds could be used as pharmacological tools to provide impor- tant information regarding platelet function. Cyclic adenosine monophosphate (c-AMP) phospho- diesterase III (PDE III) has been one of the most stud- ied targets in the search for new anti-platelet agents. 9 Among the large family of PDE III inhibitors, com- pounds containing the 3(2H)-pyridazinone ring have 0960-894X/02/$ - see front matter # 2002 Published by Elsevier Science Ltd. PII: S0960-894X(02)00246-9 Bioorganic & Medicinal Chemistry Letters 12 (2002) 1575–1577 Figure 1. § 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