Drug Rediscovery: Glybenclamide Exhibits Thromboxane Receptor Dependent Antithrombotic Activity

Abstract

Occlusive disorders such as myocardial infarction and ischemic stroke require platelet activation, a central axis being the synthesis and binding of thromboxane A2 (TXA2) to its receptor (abbreviated as TPR). There are currently no TPR antagonists available for clinical use and there are profound obstacles in translating novel formulations into a therapeutic. One solution is to investigate new uses for currently prescribed drugs, an approach termed “drug rediscovery”. To that aim, it was noticed that the sulfonylurea, glybenclamide, appears to share several pharmacophores with the TPR antagonist SQ29,548. Thus, we predicted it would interact with TPRs. It was found that glybenclamide: 1) inhibited human platelet aggregation induced by the TPR agonist U46619 (1 uM) and the TXA2 precursor arachidonic acid (0.5 mM); 2) concentration‐dependently (1–10 uM) displaced SQ29,548; 3) failed to inhibit aggregation stimulated by 15 uM ADP, or the thrombin receptor activating‐peptide 4 (40 uM); 4) failed to raise cAMP levels; 5) selectively (10mg/kg) blocked mouse TPR‐mediated aggregation ex vivo; 6) prolonged the tail bleeding time in mice; and 7) prolonged the time for occlusion in a mouse carotid artery thrombosis model. These findings indicate that glybenclamide can exert an inhibitory effect on platelet function by specifically interacting with TPR and thus has potential in the management of thrombotic disorders.