RESUMEN
Two series of new PAR1 antagonists have been identified. The first incorporates a cinnamoylpiperidine motif and the second a cinnamoylpyridine pattern. The synthesis, biological activity and structure-activity relationship of these compounds are presented. In each series, one analog showed potent in vivo antithrombotic activity in a rat AV shunt model, with up to 53% inhibition at 1.25mpk iv for compound 30.
Asunto(s)
Fibrinolíticos/química , Piperidinas/química , Piridinas/química , Receptor PAR-1/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Modelos Animales de Enfermedad , Fibrinolíticos/síntesis química , Fibrinolíticos/farmacología , Humanos , Péptidos/metabolismo , Piperidinas/síntesis química , Piperidinas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Receptor PAR-1/metabolismo , Relación Estructura-ActividadRESUMEN
Protease activated receptors (PARs) or thrombin receptors constitute a class of G-protein-coupled receptors (GPCRs) implicated in the activation of many physiological mechanisms. Thus, thrombin activates many cell types such as vascular smooth muscle cells, leukocytes, endothelial cells, and platelets via activation of these receptors. In humans, thrombin-induced platelet aggregation is mediated by one subtype of these receptors, termed PAR1. This article describes the discovery of new antagonists of these receptors and more specifically two compounds: 2-[5-oxo-5-(4-pyridin-2-ylpiperazin-1-yl)penta-1,3-dienyl]benzonitrile 36 (F 16618) and 3-(2-chlorophenyl)-1-[4-(4-fluorobenzyl)piperazin-1-yl]propenone 39 (F 16357), obtained after optimization. Both compounds are able to inhibit SFLLR-induced human platelet aggregation and display antithrombotic activity in an arteriovenous shunt model in the rat after iv or oral administration. Furthermore, these compounds are devoid of bleeding side effects often observed with other types of antiplatelet drugs, which constitutes a promising advantage for this new class of antithrombotic agents.
Asunto(s)
Fibrinolíticos/síntesis química , Inhibidores de Agregación Plaquetaria/síntesis química , Receptor PAR-1/antagonistas & inhibidores , Animales , Descubrimiento de Drogas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Fibrinolíticos/administración & dosificación , Humanos , Piperazinas/farmacología , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/farmacología , Piridinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
A novel series of compounds, derived from 4-amino-phenyl piperazine, has been designed to selectively inhibit farnesyl protein transferase (FPTase) as CAAX tetrapeptide analogues. Certain of these compounds were shown to possess low nanomolar inhibitory activity both against the isolated enzyme and in cultured cells.