An inhibitor of prostacyclin biosynthesis derived from aminopyridazine

The effects of 3-dimethylamino 5-(3′ trifluoromethylbenzylidene) 6-methyl (4H)-pyridazine (PC88) on the biosynthesis of PGI₂, using horse aorta microsomes as a source of enzyme and arachidonic acid as a substrate, were investigated. Under the experimental conditions adopted, PC88 was shown to dosedependently inhibit PGI₂ biosynthesis (ID50 = 6.9×10⁻⁴ M ± 1.87 × 10⁻⁷ M). This inhbitory effect of PC88 was complex: it was of neither competitive nor non-competitive type. 3-dimethylamino 5-(2′,6′-dichlorobenzylidene 6-methyl-(4H)-pyridazine (PC89) enhanced the biosynthesis of PGI₂. It is worth noticing the replacement of the 2 Cl at carbon atoms 1 and 4 by a CF₃ at carbon atom 2 of the phenol ring. This appears to reverse the activity of the molecule on the synthesis of PGI₂. PC88 and PC89 were both inhibitors of TXA₂ synthetase.