title: Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization.
abstract: Platelet aggregation is one of the main events involved in vascular thrombus formation. Recently, N'-substituted-phenylmethylene-3-methyl-1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine-4-carbohydrazides were described as antiplatelet derivatives. In this work, we explore the properties of these antiplatelet agents through a series of pharmacological, biochemical and toxicological studies. The antiplatelet activity of each derivative was confirmed as 3a, 3b and 3 h significantly inhibited human platelet aggregation induced by arachidonic acid, with no detectable effect on clotting factors or healthy erythrocytes. Importantly, mice treated with derivative 3a showed a higher survival rate at an in vivo model of pulmonary thromboembolism with a lower bleeding risk in comparison to aspirin. The in silico studies pointed a series of structural parameters related to thromboxane synthase (TXS) inhibition by 3a, which was confirmed by tracking plasma levels of PGE2 and TXB2 through an in vitro enzyme immunoassay. Derivative 3a showed selective TXS inhibition allied with low bleeding risk and increased animal survival, revealing the derivative as a promising candidate for treatment of cardiovascular diseases.
authors.affiliation: a Laboratório de Antibióticos , Bioquímica, Ensino e Modelagem Molecular (LABiEMol) - Instituto de Biologia, Universidade Federal Fluminense , Niterói , Brazil .|b Programa de Pós-Graduação em Patologia (PPG-UFF) - Hospital Universitário Antônio Pedro, Universidade Federal Fluminense , Niterói , Brazil .
authors.forename: Max Seidy
authors.initials: MS
authors.lastname: Saito
authors.affiliation: a Laboratório de Antibióticos , Bioquímica, Ensino e Modelagem Molecular (LABiEMol) - Instituto de Biologia, Universidade Federal Fluminense , Niterói , Brazil .|b Programa de Pós-Graduação em Patologia (PPG-UFF) - Hospital Universitário Antônio Pedro, Universidade Federal Fluminense , Niterói , Brazil .
authors.forename: André Luiz
authors.initials: AL
authors.lastname: Lourenço
authors.affiliation: c Laboratório de Química Medicinal (LQMed) - Faculdade de Farmácia , Universidade Federal Fluminense , Niterói , Brazil .
authors.forename: Luiza Rosaria Sousa
authors.initials: LR
authors.lastname: Dias
authors.affiliation: c Laboratório de Química Medicinal (LQMed) - Faculdade de Farmácia , Universidade Federal Fluminense , Niterói , Brazil .
authors.forename: Antônio Carlos Carreira
authors.initials: AC
authors.lastname: Freitas
authors.affiliation: a Laboratório de Antibióticos , Bioquímica, Ensino e Modelagem Molecular (LABiEMol) - Instituto de Biologia, Universidade Federal Fluminense , Niterói , Brazil .
authors.forename: Maíra Ingrid
authors.initials: MI
authors.lastname: Vitorino
authors.affiliation: d Laboratório de Modelagem Molecular (LabMMol) - Instituto de Química .
authors.forename: Magaly Girão
authors.initials: MG
authors.lastname: Albuquerque
authors.affiliation: e Laboratório de Modelagem Molecular e QSAR (ModMolQSAR) - Faculdade de Farmácia , and.
authors.forename: Carlos Rangel
authors.initials: CR
authors.lastname: Rodrigues
authors.affiliation: f Laboratório de Tecnologia Industrial Farmacêutica (LabTIF) - Faculdade de Farmácia , Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil.
authors.forename: Lúcio Mendes
authors.initials: LM
authors.lastname: Cabral
authors.affiliation: b Programa de Pós-Graduação em Patologia (PPG-UFF) - Hospital Universitário Antônio Pedro, Universidade Federal Fluminense , Niterói , Brazil .
authors.forename: Eliane Pedra
authors.initials: EP
authors.lastname: Dias
authors.affiliation: a Laboratório de Antibióticos , Bioquímica, Ensino e Modelagem Molecular (LABiEMol) - Instituto de Biologia, Universidade Federal Fluminense , Niterói , Brazil .|b Programa de Pós-Graduação em Patologia (PPG-UFF) - Hospital Universitário Antônio Pedro, Universidade Federal Fluminense , Niterói , Brazil .
authors.forename: Helena Carla
authors.initials: HC
authors.lastname: Castro
authors.affiliation: a Laboratório de Antibióticos , Bioquímica, Ensino e Modelagem Molecular (LABiEMol) - Instituto de Biologia, Universidade Federal Fluminense , Niterói , Brazil .|f Laboratório de Tecnologia Industrial Farmacêutica (LabTIF) - Faculdade de Farmácia , Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil.
authors.forename: Plínio Cunha
authors.initials: PC
authors.lastname: Satlher
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine
keywords: Antihemostatic; antiplatelet; molecular modeling; pyrazolopyridine derivatives; thrombosis