Synthesis and pharmacological evaluation of peptide-mimetic protease-activated receptor-1 antagonists containing novel heterocyclic scaffolds.
Protease-activated receptor-1 (PAR-1) is a G-coupled receptor activated by alpha-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.
Severino
Beatrice
B
Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli Federico II Via D. Montesano, 49, 80131 Napoli, Italy.
Fiorino
Ferdinando
F
Perissutti
Elisa
E
Frecentese
Francesco
F
Cirino
Giuseppe
G
Roviezzo
Fiorentina
F
Santagada
Vincenzo
V
Caliendo
Giuseppe
G
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D018716:Molecular Mimicry; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors
D006571:Heterocyclic Compounds; D007211:Indoles; D010455:Peptides; D011480:Protease Inhibitors; D010975:Platelet Aggregation Inhibitors