Inhibitory Effects of TA-993, a New 1,5-Benzothiazepine Derivative, on Platelet Aggregation

Abstract

Abstract TA-993, an l - cis 4′,8-dimethyl derivative of the Ca 2+ antagonist diltiazem, and some of its metabolites inhibited platelet aggregation induced by collagen, ADP, epinephrine, platelet activating factor, arachidonic acid, and U-46619 in human platelets in vitro. Among the metabolites, MB3 was the most potent (IC 50 , <1 μmol/L; several hundred times more potent than the parent compound). The d isomer of MB3 was >100 times less potent than the l isomer. Unlike acetylsalicylic acid (ASA), TA-993 inhibited both primary and secondary phases of ADP-induced platelet aggregation and also exhibited a disaggregating effect on human platelet aggregates. The inhibitory effect of TA-993 was enhanced when used in combination with ASA. In ex vivo studies involving rats, TA-993 (≈0.3 to 100 mg/kg PO) dose-dependently inhibited collagen-induced platelet aggregation (ED 50 , 3 mg/kg PO). In the whole-blood platelet aggregation system in rats, orally administered TA-993 was also inhibitory in single (3 to 30 mg/kg) or repeated daily (10 mg/kg per day for 10 days) dosage. Orally administered TA-993 dose-dependently inhibited ADP-induced platelet aggregation ex vivo in dogs (0.3 to 10 mg/kg), significantly protected mice against collagen+epinephrine–induced thromboembolic death (10 mg/kg), and inhibited thrombus formation in an arteriovenous shunt in rats (30 mg/kg). The Ca 2+ -antagonistic action of TA-993 was very weak in depolarized canine basilar arteries: the potency was ≈1/10 that of diltiazem ( d - cis ) and d -TA-993. These results suggest that antiplatelet action is more characteristic of the l - cis than the d - cis 1,5-benzothiazepine structure and that TA-993 may become a clinically useful antiplatelet agent of this structure series.