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 vitro 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 ≃ aspalatone > ticlopidine. A single dose of asplatone 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. In addition, aspalatone caused negligible gastric mucosal damage (ulcer index = 0.71 mm, 800 mg/kg p.o.) in a sharp contrast to ulcerogenic ASA (ulcer index = 29 mm, 200 mg/kg p.o.) Antioxidant activity of aspalatone was comparable to that of maltol; IC₅₀ values for malondialdehyde degeneration in vitro were 1.1 x 10^-4 mol/l and 8.4 x 10^-5 mol/l, respectively. These results suggest that aspalatone might be a potential antithrombotic agent with low ulcerogenicity.