Oral antithrombotic effects of acylhydrazone derivatives

Aim: in the search for new antithrombotic drug candidates,the synthesis and anti-platelet activity of a new series of n-acylhydrazones that were designed as thrombin inhibitors has been previously described. the aim of this work was to further characterize the effects of these compounds on thrombin- induced platelet aggregation and induced thrombosis in vivo. methods: in this work,four compounds were tested,lassbio-693,694,743 and 752,on platelet aggregation induced by thrombin,adp and trap-4a. these compounds were further tested using a mouse pulmonary thromboembolism model induced by collagen (500 μg/kg) and norepinephrine (80 μg/kg) or thrombin (2,000 ui),and a deep venous thrombosis model. results: at 200 μm,the compounds showed between 36% and 82% inhibition (for l-743 and l-752,respectively) of thrombin-induced platelet aggregation. the receptor agonist of par-4,trap-4a (250 μm),was used and inhibition between 43% and 77% was observed for each compound (200 μm). compounds lassbio-752 and 743 were the most effective in the venous thrombosis model,increasing the survival of the treated animals to 63% and 46%,respectively,in the model of collagen-induced thromboembolism and increasing to 80% (both) in the thrombin-induced model. lassbio 743 was more effective for deep vein thrombosis,reducing the weight of the thrombus by approximately 70%. conclusion: all compounds were administered orally and have shown effective antithrombotic action independently of the thrombotic stimulus. these results indicate that compounds lassbio-743 and 752 are potential candidates for the treatment of cardiovascular diseases.