CGS 12970: a novel, long acting thromboxane synthetase inhibitor

Abstract

1 CGS 12970 is a potent selective inhibitor of human platelet thromboxane synthestase in vitro (IC50 = 12 nM). It is four orders of magnitude less potent as an inhibitor of sheep seminal vesicle cyclooxygenase, bovine aorta prostacyclin synthetase and human leucocyte 15-lipoxygenase. 2 The compound inhibited collagen-induced thromboxane B2 production by human platelets in vitro without an effect on the accompanying platelet aggregation induced by collagen, ADP, platelet activating factor, thrombin, arachidonic acid or the prostaglandin mimetic, U 46619. 3 Administration of CGS 12970 to rats inhibited collagen-induced thromboxane B2 production but had no effect on platelet aggregation ex vivo. It also had no effect on platelet aggregation induced by thrombin or on plasma clotting times. 4 A single oral dose of 1 or 3 mg kg-' to rabbits inhibited thromboxane B2 production in clotting blood ex vivo for 12 or 24 h respectively. 5 CGS 12970 inhibited thromboxane B2 production in vivo induced by intravenous administration of collagen to rats or calcium ionophore to guinea-pigs. In both cases there was a concomitant elevation of immunoreactive 6-keto-prostaglandin Flr. but no effect on the induced thrombocytopenia.6 As with other thromboxane synthetase inhibitors, CGS 12970 prolonged tail bleeding time in the rat. However, CGS 12970 was not as potent as other thromboxane synthetase inhibitors in this test. 7 In addition to these usual effects of thromboxane synthetase inhibitors, CGS 12970 inhibited the thrombocytopenia induced by the Forssman reaction or ADP administration. In these tests the effect of the compound was of short duration. 8 CGS 12970 had no effect on the thrombocytopenia associated with the Arthus reaction which distinguishes it from cyclo-oxygenase inhibitors. It also had no effect on thrombus formation on a cotton thread in an arteriovenous shunt in the rat.

Failure of Thromboxane Synthetase Inhibition to Protect the Postinfarcted Heart against the Induction of Ventricular Tachycardia and Ventricular Fibrillation in a Conscious Canine Model of Sudden Coronary Death

“…In studies conducted in dogs, CGS 13080 and U 63,557 were found to inhibit arachidonic-acid-induced platelet aggrega tion while having no effect on collagen-or ADP-induced platelet aggregation [24,25], In contrast, Schumacher and Lucchesi [36] found that thromboxane synthetase inhibiton with dazoxiben (U 37,248) inhibited platelet aggregation to both ADP and colla gen, while Shea et al [37] showed that the thromboxane synthetase inhibitor OKY 1581 attenuated platelet aggregation to colla gen, ADP and arachidonic acid. Previous investigations with CGS 12970 using human and rat platelets showed that this compound did not inhibit platelet aggregation to a vari ety of agonists including collagen, ADP, ara chidonic acid, thrombin and platelet activat ing factor [38]. In the present investigation, treatment with CGS 12970 was found to attenuate significantly the aggregation in duced by arachidonic acid while not affect ing aggregation to collagen or ADP.…”

Mediation of bradykinin‐induced contraction in canine veins via thromboxane/prostaglandin endoperoxide receptor activation

“…The first inhibitor, dazoxiben (Randall et al, 1981), had no significant (P < 0.05) inhibitory effects on BK (10-6M)-induced contraction in either vein at 10-SM or 1O-4M (Table 1). Similarly, the maximum BK-induced contraction was not reduced by CGS12970 (10-5M), a second more potent thromboxane synthase inhibitor (Ambler et al, 1985) (Table 1). In general, inhibition of thromboxane synthase, and hence of thromboxane production, did not significantly decrease the contractile response to BK in canine jugular and femoral vein.…”

Thromboxane Inhibitors Attenuate Inflammatory and Fibrotic Changes in Rat Liver Despite Continued Ethanol Administrations

“…The TXSI (CGS 12970; Novartis, Summit, NJ) was administered at a dose of 10 mg/kg/d as a bolus through the intragastric tube. CGS 12970 is a long‐acting inhibitor of thromboxane production in vivo and has no effect on cyclooxygenase or lipooxygenase (Ambler et al., ).…”