2. Academic Validation
  3. Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization

Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization

  • J Enzyme Inhib Med Chem. 2016 Dec;31(6):1591-601. doi: 10.3109/14756366.2016.1158712.
Max Seidy Saito 1 2,  André Luiz Lourenço 1 2,  Luiza Rosaria Sousa Dias 3,  Antônio Carlos Carreira Freitas 3,  Maíra Ingrid Vitorino 1,  Magaly Girão Albuquerque 4,  Carlos Rangel Rodrigues 5,  Lúcio Mendes Cabral 6,  Eliane Pedra Dias 2,  Helena Carla Castro 1 2,  Plínio Cunha Satlher 1 6
Affiliations

Affiliations

  • 1 a Laboratório de Antibióticos , Bioquímica, Ensino e Modelagem Molecular (LABiEMol) - Instituto de Biologia, Universidade Federal Fluminense , Niterói , Brazil .
  • 2 b Programa de Pós-Graduação em Patologia (PPG-UFF) - Hospital Universitário Antônio Pedro, Universidade Federal Fluminense , Niterói , Brazil .
  • 3 c Laboratório de Química Medicinal (LQMed) - Faculdade de Farmácia , Universidade Federal Fluminense , Niterói , Brazil .
  • 4 d Laboratório de Modelagem Molecular (LabMMol) - Instituto de Química .
  • 5 e Laboratório de Modelagem Molecular e QSAR (ModMolQSAR) - Faculdade de Farmácia , and.
  • 6 f Laboratório de Tecnologia Industrial Farmacêutica (LabTIF) - Faculdade de Farmácia , Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil.
PMID: 27000933 DOI: 10.3109/14756366.2016.1158712
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.

Keywords

Antihemostatic; antiplatelet; molecular modeling; pyrazolopyridine derivatives; thrombosis.

Figures
Products