title: Novel thienylacylhydrazone derivatives inhibit platelet aggregation through cyclic nucleotides modulation and thromboxane A2 synthesis inhibition.
abstract: The aim of this study has been to investigate the antiplatelet activity of a new series of thienylacylhydrazone derivatives analogous to the lead compound LASSBio-294 ((2-thienylidene) 3,4-methylenedioxybenzoylhydrazine). The antiplatelet effect was investigated in rabbit and human platelet rich plasma stimulated by arachidonic acid, collagen, ADP and in washed platelet stimulated by thrombin. The effects on the production of cyclic nucleotides and thromboxane A(2) (TXA(2)) in human platelets were also investigated. Compounds LASSBio-785 (N-Methyl (2-thienylidene) 3,4-methylenedioxybenzoylhydrazine), LASSBio-786 (N-Benzyl (2-thienylidene) 3,4-methylenedioxybenzoylhydrazine), LASSBio-787 ((5-Methyl-2-thienylidene) 3,4-methylenedioxybenzoylhydrazine), LASSBio-788 (N-Allyl (2-thienylidene) 3,4-methylenedioxybenzoylhydrazine) and LASSBio-789 ((5-Bromo-2-thienylidene) 3,4-methylenedioxybezoylhydrazine) inhibited platelet aggregation induced by arachidonic acid, collagen and ADP. LASSBio-785, LASSBio-788 and LASSBio-789 presented the higher potency in platelet aggregation induced by arachidonic acid (IC(50) values of 0.3, 0.2 and 3.1 microM, respectively) and collagen (IC(50) values of 0.9, 1.5 and 3.4 microM, respectively), with a 20 to 70-fold increase in potency compared to LASSBio-294. They inhibited the ATP release reaction by 95%, the whole blood aggregation by 35-45% and the TXB(2) production was totally abolished. In addition, they presented a significant effect on bleeding time. Qualitative studies in thrombin-induced washed platelet aggregation in the presence of sodium nitroprusside (SNP) suggested a phosphodiesterase-2 (PDE2) like effect for LASSBio-785, LASSBio-788 and LASSBio-789. They were able to increase the cGMP levels in non-stimulated platelets, in SNP-stimulated platelets and in the presence of 1-H- [1, 2, 4] oxadiazolo [4, 3- a] quinoxalin- 1- one (ODQ). The antiplatelet aggregation activity exerted by thienylacylhydrazone derivatives seems to be related to cyclic nucleotides regulation and TXA(2) synthesis inhibition. The structural modification of compound LASSBio-294 led to the optimization of its pharmacological properties and to the discovery of new potent antiplatelet prototypes with an antithrombotic potential.
authors.affiliation: Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Departamento de Fármacos, Universidade Federal do Rio de Janeiro (UFRJ), Centro de Ciências da Saúde (CCS), P.O. Box 68006, Ilha do Fundão, 21941-902, Rio de Janeiro, RJ, Brazil.
authors.forename: Fernanda C F
authors.initials: FC
authors.lastname: Brito
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Kummerle
authors.forename: Claire
authors.initials: C
authors.lastname: Lugnier
authors.forename: Carlos A M
authors.initials: CA
authors.lastname: Fraga
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: Ana L P
authors.initials: AL
authors.lastname: Miranda
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009712:Nucleotides, Cyclic / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D006835:Hydrazones; C439284:LASSBio 294; D009712:Nucleotides, Cyclic; D010975:Platelet Aggregation Inhibitors; D013876:Thiophenes; D016718:Arachidonic Acid; D013928:Thromboxane A2; D003094:Collagen; D010727:Phosphoric Diester Hydrolases; D013917:Thrombin