title: Oral antithrombotic effects of acylhydrazone derivatives.
abstract: OBJECTIVE
  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%.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratório de Hemostase e Venenos LabHemoVen, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Flávia Serra
authors.initials: FS
authors.lastname: Frattani
authors.forename: Eduardo Oliveira
authors.initials: EO
authors.lastname: Coriolano
authors.forename: Lidia Moreira
authors.initials: LM
authors.lastname: Lima
authors.forename: Eliezer Jesus
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: Russolina Benedeta
authors.initials: RB
authors.lastname: Zingali
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D006835:Hydrazones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011655:Pulmonary Embolism / Q000188:drug therapy
chemical_list: D000991:Antithrombins; D006835:Hydrazones; D010975:Platelet Aggregation Inhibitors