Synthesis, hydrolysis kinetics and anti-platelet effects of isosorbide mononitrate derivatives of aspirin

Abstract

Two isomeric aspirin derivatives of isosorbide-5-mononitrate (ISMN) were prepared and evaluated as potential mutual prodrugs of aspirin and nitric oxide. The hydrolysis of both compounds was studied in pH 7.4 phosphate buffer solution, buffered α-chymotrypsin solution and 10% buffered rabbit plasma. The benzodioxin-4-one derivative was hydrolysed to salicylic acid and ISMN acetate in buffer solution ( t 1/2 32.1 h), 10% buffered rabbit plasma ( t 1/2 25.7 min) and α-chymotrypsin ( t 1/2 86.6 min). The carboxylic acid ester derivative ISMNA was hydrolysed via the salicylate ester in buffer solution ( t 1/2 48.5 h) but was rapidly and almost exclusively hydrolysed to aspirin and ISMN in plasma solution ( t 1/2 2.8 min). The hydrolysis appeared to be enzyme mediated as it was suppressed by co-incubation with eserine. ISMNA was evaluated for its ability to inhibit platelet aggregation in rabbit PRP in response to the following agonists: arachidonic acid (AA) (100 μM), ADP (1.2 μM), phorbol ester (0.5 μM), platelet activating factor (PAF) (5 nM) and the thromboxane mimic U46619 (1.5 μM). ISMNA suppressed platelet response to AA at 1 μM whereas 10 μM aspirin showed no inhibitory effects.