RS-5186, a novel thromboxane synthetase inhibitor with a potent and extended duration of action.
RS-5186, sodium 6-[2-[1-(1H)-imidazolyl]methyl-4,5-dihydrobenzo[b]thiophene]- carboxylate, inhibited platelet thromboxane A2 (TXA2) synthetase with IC50 values of 6 nM and 13 nM for human and rabbit microsomes, respectively. It had a selectivity for TXA2 synthetase 10(5)-fold greater than that for cyclooxygenase, PGI2 synthetase, 5-lipoxygenase and phospholipase A2. When administered orally or intravenously to dogs at 1 mg/kg, RS-5186 suppressed serum TXB2 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 TXB2 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 TXB2 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 (ED50 = 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 TXA2 synthetase inhibitor with a long duration of action, and suggest that the compound could be useful in diseases where TXA2 is involved.
Ushiyama
S
S
New Lead Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Ito
T
T
Asai
F
F
Oshima
T
T
Terada
A
A
Matsuda
K
K
Yamazaki
M
M
D000818:Animals; D001095:Arachidonic Acids; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D004285:Dogs; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008861:Microsomes / Q000201:enzymology; D010976:Platelet Count; D011453:Prostaglandins / Q000097:blood; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013876:Thiophenes / Q000494:pharmacology*; D013927:Thrombosis / Q000517:prevention & control; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000097:blood
D001095:Arachidonic Acids; D011453:Prostaglandins; D013876:Thiophenes; C055806:RS 5186; D013929:Thromboxane B2; D013930:Thromboxane-A Synthase