A novel pyridobenzazepinone derivative with long lasting thromboxane synthase inhibition

A novel pyridobenzazepinone derivative (Z)-11-(5-carboxypentylidene)-6-methyl-5,11-dihydropyrido[4,3-C] [1]benzazepin-5(6H)-one (CAS 127654-03-9, KF 13218), inhibited human and bovine platelet thromboxane synthase with IC 50 values of 27 ± 5.8 nmol/l (mean ± S.E.M.) and 36±6.9 nmol/l, respectively. The compound did not inhibit cyclooxygenase or 5-lipoxygenase up to a dose of 100 μmol/l and did not antagonize thromboxane A 2 /prostaglandin H 2 receptors. KF13218 inhibited arachidonic acid-induced thromboxane B 2 production by human intact platelets with an IC 50 value of 5.3±1.3 nmol/l. The IC 50 value of KF13218 for the intact platelets was about 5 times lower than that for the microsomal enzyme. The inhibition of thromboxane synthase in platelets by KF13218 was sustained after removal of the extracellular compound. After oral dosing in rat from 0.03 mg/kg to 3 mg/kg, KF13218 dose-dependently inhibited the thromboxane B 2 production in serum, and the inhibition was retained for 72 h. KF13218, at a dose of 0.1 mg/kg p.o. prevented mortality induced by sodium arachidonate in rabbit. It is concluded that KF13218 is a potent, selective and long lasting thromboxane synthase inhibitor.