RS-5186, a novel thromboxane synthetase inhibitor with a potent and extended duration of action.

Abstract RS-5186, sodium 6-[2-[1-(1H)-imidazolyl]methyl-4,5-dihydrobenzo[b]thiophene]-carboxylate, inhibited platelet thromboxane A 2 (TXA 2 ) synthetase with IC 50 values of 6 nM and 13 nM for human and rabbit microsomes, respectively. It had a selectivity for TXA 2 synthetase 10 5 -fold greater than that for cyclooxygenase, PGI 2 synthetase, 5-lipoxygenase and phospholipase A 2 . When administered orally or intravenously to dogs at 1 mg/kg, RS-5186 suppressed serum TXB 2 levels almost completely with sustained duration of action: the suppression during 0.5 hr to 8 hr after dosing was more than 90%, and was 70 – 80% at 24 hr. Similar suppression of serum TXB 2 levels was observed in rats and rabbits. Such suppression by RS-5186 was more potent than that by OKY-046 and CV-4151. Serial administration of RS-5186 (0.1 mg/kg/ day p.o.) to dogs for 7 days decreased the serum TXB 2 levels constantly during the medication, and no rebound phenomenon was observed after the medication was stopped. In a thrombotic model induced by sodium arachidonate injection in rabbits, RS-5186 at 1 mg/kg p.o. completely protected against sudden death (ED 50 = 0.12 mg/kg, 1 hr after dosing) and this protective effect extended over 8 hr. All these results show that RS-5186 is a potent and highly selective TXA 2 synthetase inhibitor with a long duration of action, and suggest that the compound could be useful in diseases where TXA 2 is involved.