A NOVEL PYRIDOBENZAZEPINONE DERIVATIVE WITH LONG-LASTING THROMBOXANE SYNTHASE INHIBITION

A novel pyridobenzazepinone derivative (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 w ith IC50 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 mu mol/l and did not antagonize thro mboxane A(2)/prostaglandin H-2 receptors. KF13218 inhibited arachidoni c acid-induced thromboxane B-2 production by human intact platelets wi th an IC50 value of 5.3 +/- 1.3 nmol/l. The IC50 value of KF13218 for the intact platelets was about 5 times lower. than that for the micros omal enzyme. The inhibition of thromboxane synthase in platelets by KF 13218 was sustained after removal of the extracellular compound. After oral dosing in rat from 0.03 mg/kg to 3 mg/kg, KF13218 dose-dependent ly inhibited the thromboxane B-2 production in serum, and the inhibiti on was retained for 72 h. KF13218, at a dose of 0.1 mg/kg p.o. prevent ed mortality induced by sodium arachidonate in rabbit. It is concluded that KF13218 is a potent, selective and long lasting thromboxane synt hase inhibitor.