RESUMEN
Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.
Asunto(s)
Compuestos de Fenilurea/química , Inhibidores de Agregación Plaquetaria/química , Antagonistas del Receptor Purinérgico P2Y/química , Receptores Purinérgicos P2Y1/química , Tiazoles/química , Urea/análogos & derivados , Administración Oral , Animales , Perros , Semivida , Macaca fascicularis , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Antagonistas del Receptor Purinérgico P2Y/farmacocinética , Antagonistas del Receptor Purinérgico P2Y/farmacología , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Ratas , Receptores Purinérgicos P2Y1/metabolismo , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacología , Tiazoles/uso terapéutico , Trombosis/tratamiento farmacológico , Urea/farmacocinética , Urea/farmacología , Urea/uso terapéuticoRESUMEN
A number of new amine scaffolds with good inhibitory activity in the ADP-induced platelet aggregation assay have been found to be potent antagonists of the P2Y1 receptor. SAR optimization led to the identification of isoindoline 3c and piperidine 4a which showed good in vitro binding and functional activities, as well as improved aqueous solubility. Among them, the piperidine 4a showed the best overall profile with favorable PK parameters.
Asunto(s)
Aminas/química , Agonistas del Receptor Purinérgico P2Y/química , Receptores Purinérgicos P2Y1/química , Urea/análogos & derivados , Adenosina Difosfato/farmacología , Aminas/síntesis química , Aminas/farmacocinética , Animales , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Semivida , Humanos , Microsomas Hepáticos/metabolismo , Piperidinas/química , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacocinética , Unión Proteica , Agonistas del Receptor Purinérgico P2Y/síntesis química , Agonistas del Receptor Purinérgico P2Y/farmacocinética , Ratas , Receptores Purinérgicos P2Y1/metabolismo , Relación Estructura-Actividad , Urea/síntesis química , Urea/farmacocinéticaRESUMEN
Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.
Asunto(s)
Diseño de Fármacos , Conformación Molecular , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/farmacocinética , Antagonistas del Receptor Purinérgico P2Y/farmacología , Antagonistas del Receptor Purinérgico P2Y/farmacocinética , Receptores Purinérgicos P2Y1/metabolismo , Compuestos de Espiro/farmacología , Compuestos de Espiro/farmacocinética , Urea/farmacología , Urea/farmacocinética , Animales , Disponibilidad Biológica , Humanos , Indoles/química , Modelos Moleculares , Compuestos de Fenilurea/química , Compuestos de Fenilurea/metabolismo , Antagonistas del Receptor Purinérgico P2Y/química , Antagonistas del Receptor Purinérgico P2Y/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Purinérgicos P2Y1/química , Homología de Secuencia de Aminoácido , Compuestos de Espiro/química , Compuestos de Espiro/metabolismo , Urea/química , Urea/metabolismoRESUMEN
Five-membered-ring heterocyclic urea mimics have been found to be potent and selective antagonists of the P2Y1 receptor. SAR of the various heterocyclic replacements is presented, as well as side-chain SAR of the more potent thiadiazole ring system which leads to thiadiazole 4c as a new antiplatelet agent.
Asunto(s)
Antagonistas del Receptor Purinérgico P2Y/química , Antagonistas del Receptor Purinérgico P2Y/farmacología , Receptores Purinérgicos P2Y1/química , Tiadiazoles/química , Tiadiazoles/farmacología , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Humanos , Cinética , Unión Proteica , Relación Estructura-Actividad , Urea/químicaRESUMEN
We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure-activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models.