title: New pyrazolylhydrazone derivatives as inhibitors of platelet aggregation.
abstract: A series of 5-pyrazolylhydrazone derivatives was designed to be mixed hybrid isosteres of both BW755C and CBS-1108, which belong to the class of dual cyclo-oxygenase and 5-lipoxygenase inhibitors. Some derivatives of this series inhibit the in-vitro platelet aggregation of citrated platelet-rich rabbit plasma induced by ADP (5 microM), collagen (5 micrograms mL-1) and arachidonic acid (100 microM). The structure-activity relationships of this class of compounds were determined from these results. When ADP is used as the aggregation inducer, the presence of free oxygenated substituents at the p-position in the phenyl subunit of the hydrazone moiety favours inhibitory activity; p-methoxyformylbenzene-5-(1-phenyl-3-methyl-4-nitropyrazolyl )hydrazone (100 microM), which has a methoxy group at this position was the most active with 62.8% inhibition of aggregation. In contrast, substitution in the aryl ring does not affect the aggregation induced by collagen, whereas the non-substituted compound, formylbenzene-5-(1-phenyl-3-methyl-4-nitropyrazolyl)hydra zon e, showed similar activity to those of substituted derivatives. In the arachidonic acid assays, the presence of an aryl ring linked to the hydrazone moiety, with an adequate electronic density at the ring due to the nature of its substituents, is an important structural requirement for inhibitory activity.
authors.affiliation: Departamento de Farmacologia Básica e Clinica, Universidade Federal do Rio de Janeiro, Brasil.
authors.forename: I A
authors.initials: IA
authors.lastname: da Silveira
authors.forename: L G
authors.initials: LG
authors.lastname: Paulo
authors.forename: A L
authors.initials: AL
authors.lastname: de Miranda
authors.forename: S O
authors.initials: SO
authors.lastname: Rocha
authors.forename: A C
authors.initials: AC
authors.lastname: Freitas
authors.forename: E J
authors.initials: EJ
authors.lastname: Barreiro
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D006835:Hydrazones / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D006835:Hydrazones; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D016718:Arachidonic Acid; D000244:Adenosine Diphosphate; D003094:Collagen; D007213:Indomethacin; D004121:Dimethyl Sulfoxide