title: A novel pyridobenzazepinone derivative with long lasting thromboxane synthase inhibition.
abstract: A novel pyridobenzazepinone derivative (Z)-11-(5-carboxypentylidene)-6-methyl-5, 11-dihydropyrido +ad4,3-C] [1] benzazepin-5 (6H)-one (CAS 127654-03-9, KF 13218), inhibited human and bovine platelet thromboxane synthase with 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 mumol/l and did not antagonize thromboxane A2/prostaglandin H2 receptors. KF13218 inhibited arachidonic acid-induced thromboxane B2 production by human intact platelets with 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 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 B2 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.
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Miki
authors.forename: N
authors.initials: N
authors.lastname: Kishibayashi
authors.forename: M
authors.initials: M
authors.lastname: Takeda
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: H
authors.initials: H
authors.lastname: Obase
authors.forename: A
authors.initials: A
authors.lastname: Ishii
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity; D001552:Benzazepines / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D002417:Cattle; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003645:Death, Sudden; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
chemical_list: D001552:Benzazepines; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D011982:Receptors, Prostaglandin; C098445:KF 13218; D016718:Arachidonic Acid; D013929:Thromboxane B2; D013930:Thromboxane-A Synthase