Nuria Fraiz

Pyridazines. Part XXIX: synthesis and platelet aggregation inhibition activity of 5-substituted-6-phenyl-3(2H)-pyridazinones. Novel aspects of their biological actions.

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.

Pyridazines. Part 28: 5-Alkylidene-6-phenyl-3(2H)-pyridazinones, a New Family of Platelet Aggregation Inhibitors §

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).

Calpain controls the balance between protein tyrosine kinase and tyrosine phosphatase activities during platelet activation

Protein phosphorylation was studied during platelet stimulation in two ranges of ionized [Ca2+]. At ionized [Ca2+]i≤1 μM, proteins were phosphorylated. At ionized [Ca2+]i≥4 μM, phosphoproteins disappeared. Protein dephosphorylation was prevented by the combined action of calpeptin and phosphatase inhibitors. Protein tyrosine phosphatase activity was stimulated regardless of the ionized [Ca2+]i level. Protein tyrosine kinase activity was stimulated at ionized [Ca2+]i≤1 μM, whereas at ionized [Ca2+]i≥4 μM, no protein tyrosine kinase activity was observed except in the presence of calpeptin. Thus, the massive tyrosine phosphoprotein disappearance observed at a high ionized [Ca2+]i resulted not only in protein tyrosine phosphatase activation, but also in calpain‐induced protein tyrosine kinase inactivation.