Short communication: Antiaggregatory activity of hypoglycaemic sulphonylureas

Abstract Aims/hypothesis. Vascular complications observed in diabetes are often related to altered platelet functions. The most widely used hypoglycaemic drugs for treating Type II (non-insulin-dependent) diabetes mellitus are sulphonylurea derivatives. The purposes of this study were to evaluate the inhibitory effects of hypoglycaemic agents on platelet aggregation, to measure their lipophilicity and identify their structural parameters which assess their antiaggregatory activity. Methods. An antiaggregatory test in vitro was carried out for 13 sulphonylurea derivatives. Aggregation of platelets, incubated with the agents at concentrations varying from 7.5 to 480 μmol/l, was induced by 10 μmol/l ADP. Drug lipophilicity parameter, log kw, was measured by gradient HPLC and the agents were subjected to molecular modelling. Results. The most pronounced inhibition of platelet aggregation was by glimepiride, gliclazide, gliquidone, glibenclamide and compound 2A. The IC25 values were 15.9, 18.6, 20.4, 28.5 and 34.7 μmol/l, respectively. Quantitative structure-activity relationships indicate that antiaggregatory activity is mainly affected by electronic and not by lipophilic properties of the agents. Conclusion/interpretation. Glimepiride appeared to be a more potent ADP-induced platelet aggregation inhibitor in vitro than gliclazide. Antiaggregatory activity was shown for gliquidone and confirmed for glibenclamide. The QSAR analysis supports the hypothesis of a free radical mechanism of action of sulphonylurea derivatives previously suggested for gliclazide.