Synthesis and pharmacological evaluation of peptide-mimetic protease-activated receptor-1 antagonists containing novel heterocyclic scaffolds

• Autor: Severino, Beatrice ; Fiorino, Ferdinando ; Perissutti, Elisa ; Frecentese, Francesco ; Cirino, Giuseppe ; Roviezzo, Fiorentina ; Santagada, Vincenzo ; Caliendo, Giuseppe
• Assuntos: Animals ; Antiplatelet effect ; Aorta, Thoracic - drug effects ; Aorta, Thoracic - physiology ; Biological and medical sciences ; Blood. Blood coagulation. Reticuloendothelial system ; Heterocyclic Compounds - chemical synthesis ; Heterocyclic Compounds - pharmacology ; Humans ; Indoles - chemical synthesis ; Indoles - pharmacology ; Male ; Medical sciences ; Molecular Mimicry ; PAR-1 ; Peptides - chemical synthesis ; Peptides - pharmacology ; Peptidomimetic ; Pharmacology. Drug treatments ; Platelet Aggregation - drug effects ; Protease Inhibitors - chemical synthesis ; Protease Inhibitors - pharmacology ; Rats ; Rats, Wistar ; Receptor, PAR-1 - antagonists & inhibitors ; Thrombin ; Vasoconstriction - drug effects
• É parte de: Bioorganic & medicinal chemistry, 2008-06, Vol.16 (11), p.6009-6020
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• Descrição: Here, we describe the synthesis and the pharmacological evaluation of novel PAR-1 peptide-mimetic antagonists characterized by the presence of new heterocyclic nuclei such as 2-methyl-indole (5- and 6-substituted) and 1,4-benzodiazepine moiety. Protease-activated receptor-1 (PAR-1) is a G-coupled receptor activated by α-thrombin and other proteases. In this paper we describe the synthesis and the pharmacological evaluation of novel peptide-mimetic antagonists (compounds 1– 16) characterized by the presence of new heterocyclic nuclei such as 2-methyl-indole (5- and 6-substituted) and 1,4-benzodiazepine moiety. The new derivatives, tested in order to evaluate their antagonist potency by using human platelet aggregation induced by PAR-1AP, resulted in some cases (compounds 1 and 4) more potent than the reference. The compounds, tested on aortic rings, confirmed the results obtained in the aggregation assay.
  
• Editor: Oxford: Elsevier Ltd
  
• Idioma: Inglês