Inhibitory effects of TA-993, a new 1,5-benzothiazepine derivative, on platelet aggregation.

Abstract

TA-993, an l-cis 4',8-dimethyl derivative of the Ca2+ 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 (IC50, <1 micromol/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 (approximately 0.3 to 100 mg/kg PO) dose-dependently inhibited collagen-induced platelet aggregation (ED50, 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 Ca2+-antagonistic action of TA-993 was very weak in depolarized canine basilar arteries: the potency was approximately 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.

• Authors: A Odawara, K Kikkawa, M Katoh, H Toryu, T Shimazaki, Y Sasaki
• Journal: Circulation research (Circ Res) Vol. 78 Issue 4 Pg. 643-9 (Apr 1996) ISSN: 0009-7330 [Print] United States
• PMID: 8635222 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Fibrinolytic Agents
• Platelet Aggregation Inhibitors
• TA 993
• Diltiazem
• Ticlopidine
• Aspirin
• Calcium

Topics

• Animals
• Aspirin (pharmacology)
• Basilar Artery (drug effects, physiology)
• Calcium (pharmacology)
• Diltiazem (analogs & derivatives, pharmacology)
• Dogs
• Dose-Response Relationship, Drug
• Electrophysiology
• Fibrinolytic Agents (pharmacology)
• Humans
• Male
• Mice
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Ticlopidine (pharmacology)
• Vasoconstriction (drug effects)