TRA-418, a novel compound having both thromboxane A2 receptor antagonistic and prostaglandin I2 receptor agonistic activities: its antiplatelet effects in human and animal platelets

Abstract

To cite this article: Yamada N, Miyamoto M, Isogaya M, Suzuki M, Ikezawa S, Ohno M, Otake A, Umemura K. TRA-418, a novel compound having both thromboxane A 2 receptor antagonistic and prostaglandin I 2 receptor agonistic activities: its antiplatelet effects in human and animal platelets. Summary. TRA-418 is a novel compound that has been found in our screening for compounds having both thromboxane A 2 (TP) receptor antagonistic and prostaglandin I 2 (IP) receptor agonistic activities. In the binding assays, TRA-418 showed a 10-fold higher af®nity to TP-receptors than IP-receptors. TRA-418 inhibited platelet aggregation induced by the TP-receptor agonist, U-46619 and by arachidonic acid at concentrations lower than those required for inhibition of ADP-induced aggregations. Furthermore, TRA-418 inhibited not only platelet aggregation induced by ADP alone, but also that induced by ADP in the presence of the TP-receptor antagonist, SQ-29548. When the IC 50 values of TRA-418 for platelet aggregation were estimated in platelet preparations from monkeys, dogs, cats, and rats using ADP and arachidonic acid as the platelet stimulating agents, it was found that the values estimated in monkey platelets were quite similar to those estimated in human platelets. In ex vivo platelet aggregation in monkeys, TRA-418 exhibited signi®cant inhibitory effects on arachidonic acidinduced aggregation in platelet preparations from monkeys treated at 3 mg kg min À1 or higher doses, where neither a signi®cant decrease in blood pressure nor a signi®cant increase in heart rate was observed. These results are consistent with the fact that TRA-418 has a relatively potent TP-receptor antagonistic activity together with a relatively weak IP-receptor agonistic activity. Prostaglandin I 2 (IP) receptor agonists have demonstrated their potent antiplatelet and antithrombotic effects in experimental animals [10,11]. In addition, IP-receptor agonists have been shown to reduce ischemic injury effectively in the acute myocardial infarction and stroke models [12±14]. Despite these useful properties as antithrombotic agents, the clinical application of IP-receptor agonists have been limited to pulmonary hypertension or moderate thrombotic disease such as arterial sclerosis obstruction because of their potent vasodilating effects [15,16].In this connection, a number of in vitro studies have reported that remarkable synergistic effects on human platelet aggregation can be observed with concomitant use of an IP-receptor agonist and a TP-receptor antagonist [17±19]. This ®nding suggests a useful application of an IP-receptor agonist in combination with a TP-receptor antagonist in vivo. In fact, we have con®rmed that concomitant use of the IP-receptor agonist, beraprost, at a limited dose effectively potentiates the antithrombotic effects of aspirin and other TP-receptor antagonists without any severe hypotension [20]. These results prompted us to screen compounds having a relatively potent TP-receptor antagonistic activity together with a relatively weak IP-...

Flavonoids inhibit platelet function through binding to the thromboxane A2 receptor

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Targeting Platelet G-Protein Coupled Receptors (GPCRs): Looking Beyond Conventional GPCR Antagonism

“…5) is a second TP receptor inhibitor that is being developed as an antiplatelet agent. TRA-418 exhibits both TP receptor antagonism and PGI 2 receptor agonism [87]. It inhibits platelet aggregation induced by ADP, TRAP, or U46619 plus epinephrine with IC 50 s of ~0.3-1.6 μM [88].…”

Investigation of a Thromboxane A 2 Receptor–Based Vaccine for Managing Thrombogenesis

“…Notably, none of the antagonists that were developed for TPR has received approval by the Food and Drug Administration; and they face important shortcomings and limitations because of frequent administration, high doses, and high costs 18, 37, 38, 55, 56, 60. In contrast, much like our passive immunization studies,19, 47 we believe that active vaccination is likely to offer a promising approach for the treatment of thrombosis.…”

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