RS-5186, sodium 6-[2-[1-(1H)-imidazolyl] methyl-4, 5-dihydrobenzo[b]thiophene] carboxylate, potently inhibited platelet microsomal thromboxane (TX) synthetase with IC50 values of 6nM for human and 13nM for rabbit microsomes, but had no effect on cyclooxygenase, PGI2 synthetase, 5-lipoxygenase and phospholipase A2 up to 300μM. When administered orally or intravenously to beagle dogs at 1mg/kg, RS-5186 suppressed the concentration of serum TXB2 almost completely with sustained duration of action; the suppression during 0.5hr to 8hr after dosing was more than 90%, and was 70-80% even at 24hr. The suppression by RS-5186 was significantly stronger than that by OKY-046 and CV-4151 at all time points. Similar results were obtained with rats and rabbits. In experimental thrombosis induced by sodium arachidonate-injection in rabbits, pretreatment with RS-5186 (1mg/kg) completely protected against sudden death, preventing an increase in the plasma TXB2 levels and thrombocytopenia. This protective effect extended over 8hr. Neither tachyphylaxis nor rebound phenomenon was observed in repeated administrations of RS-5186. All these results show that RS-5186 is a potent and highly selective TX synthetase inhibitor with a long duration of action, and suggest that the compound could be useful in diseases where TXA2 production is involved.
