PLATELET TXA2 SYNTHETASE INHIBITION AND TXA2/PROSTAGLANDIN ENDOPEROXIDE RECEPTOR BLOCKADE COMBINED IN ONE MOLECULE (R 68070)
F 68070, an oxime-alkane carboxylic acid derivative (Janssen Pharmaceutica), is a potent inhibitor of thromboxane A2 (TXA2) synthetase activity (IC50 in vitro against thrombin-stimulated human platelets in plasma : R 68070 : 2.9 x 10-8 M; CGS 13080 : 6 x 10-8 M; OKY-1581 : 8.2 x 10-8 M; dazmegrel : 2.6 x 10-8 M; dazoxiben : 2.3 x 10-8 M).The compound specifically inhibits platelet TXA2 synthetase activity (14C-arachidonic acid metabolism by washed human platelets) without effect on the cyclo-oxygenase, lipoxygenase (platelets, RBL cells) or prostacyclin synthetase activities (rat aortic rings).The inhibitory effect of R 68070 against human platelet TXA2 synthetase activity increases upon prolongation of the contact time (ICsg at 0.5 min of contact : 5.2 x 10-7 M; at 5 min : 8.3 x 10-8 M; at 30 min : 2.5 x 10-8 M) and is reversed by washing of the platelets.In vivo, the compound has a comparatively strong inhibitory effect on platelet TXA2 synthetase activity after oral administration to rats (ED50 - 2 h : R 68070 0.013 mg/kg; CGS-13080 : 0.8 mg/kg; OKY-1581 : 0.61 mg/kg; dazmegrel : 1 mg/kg; dazoxiben : 4.1 mg/kg) and a protracted duration of action in rats and dogs (inhibition 8 h after 1.25 mg/kg orally > 80 %).In vitro, R 68070 inhibits the aggregation of human platelets in plasma stimulated with collagen (IC50 : 4 x 10-6 M), but also with U 46619 (IC50 : 3.8 x 10-6 M) without affecting the primary aggregation reaction elicited by ADP, 5-HT or adrenaline. The compound thus also produces platelet TXA2/prostaglandin endoperoxide receptor blockade.In rats and in dogs R 68070 (1.25 mg/kg I.V.) potently prevents thrombus formation in carotid and coronary arteries damaged by electrical stimulation.The combination of platelet TXA2 synthetase inhibition with TXA2/prostaglandin endoperoxide blockade in one molecule thus might offer an improved anti-thrombotic effectiveness.