Synthesis and antiplatelet effects of the new antithrombotic agent aspalatone with low ulcerogenicity.
A new compound, aspalatone (acetylsalicylic acid maltol ester), was synthesized by esterification of acetylsalicylic acid (ASA) and maltol, an antioxidant, and studied for its bleeding time prolongation effect in rats, for its antiplatelet aggregation activity in vitro and ex vivo in rats, and for its antithrombotic activity in vivo using the mouse thromboembolism test. Aspalatone treatment (15 mg/kg p.o.) for 10 days prolonged bleeding time by 57% (p < 0.005) in Sprague-Dawley rats vs control, while ASA treatment (15 mg/kg p.o.) prolonged by 44%. At the low dose of 15 mg/kg p.o. at least 8 days of treatment were necessary for aspalatone and ASA to prolong the bleeding time significantly. On the other hand, salicylic acid maltol ester which lacks the acetyl group did not significantly affect bleeding time at a dose of 15 mg/kg. Aspalatone produced a potent inhibition of collagen-induced platelet aggregation in vitro with IC50 of 1.8 x 10(-4) mol/l, but, similar to ASA, did not significantly inhibit ADP-induced aggregation. The ability of oral aspalatone to inhibit platelet aggregation in rats ex vivo was compared with other reference antiplatelet drugs. Relative potency was ASA > dipyridamole approximately equal to aspalatone > ticlopidine. A single dose of aspalatone potently prevented death due to collagen-induced platelet aggregation in mice in vivo with ED50 value of 32 mg/kg p.o., but failed to prevent death due to ADP-induced platelet aggregation. When given for 10 days, aspalatone prevented collagen-induced death by 90% (p < 0.001) at 20 mg/kg, and this antithrombotic effect lasted after 4 days of wash-out period.(ABSTRACT TRUNCATED AT 250 WORDS)
Han
B H
BH
Natural Products Research Institute, Seoul National University, Korea.
Suh
D Y
DY
Yang
H O
HO
Park
Y H
YH
Kang
Y H
YH
Kim
Y C
YC
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001241:Aspirin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D001760:Bleeding Time; D003094:Collagen / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced*
D000975:Antioxidants; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D000244:Adenosine Diphosphate; D003094:Collagen; C091320:aspalatone; D001241:Aspirin