Inhibitory effects of TA-993, a new 1,5-benzothiazepine derivative, on platelet aggregation.
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.
Odawara
A
A
Pharmacological Research Laboratory, Tanabe Seiyaku Co, Ltd, Toda, Japan.
Kikkawa
K
K
Katoh
M
M
Toryu
H
H
Shimazaki
T
T
Sasaki
Y
Y
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001488:Basilar Artery / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000494:pharmacology; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013988:Ticlopidine / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; C097363:TA 993; D004110:Diltiazem; D013988:Ticlopidine; D001241:Aspirin; D002118:Calcium