RESUMEN
The synthesis and biological activity of novel glycoprotein IIb-IIla antagonists containing the 3,9-diazaspiro[5.5]undecane nucleus are described. The potent activity of these compounds as platelet aggregation inhibitors demonstrates the utility of the spirocyclic structures as a central template for nonpeptide RGD mimics.
Asunto(s)
Inhibidores de Agregación Plaquetaria/síntesis química , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Compuestos de Espiro/síntesis química , Administración Oral , Animales , Compuestos Aza/síntesis química , Compuestos Aza/farmacocinética , Compuestos Aza/farmacología , Disponibilidad Biológica , Plaquetas/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Ratas , Ratas Sprague-Dawley , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
The synthesis and biological activity of novel glycoprotein IIb-IlIa anatagonists containing 3-azaspiro[5.5]undec-9-yl nucleus are described. The potent activity of these compounds as platelet aggregation inhibitors demonstrates the utility of the monoazaspirocyclic structure as central template for nonpeptide RGD mimics.
Asunto(s)
Inhibidores de Agregación Plaquetaria/síntesis química , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Compuestos de Espiro/síntesis química , Administración Oral , Animales , Compuestos Aza/síntesis química , Compuestos Aza/farmacocinética , Compuestos Aza/farmacología , Disponibilidad Biológica , Plaquetas/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Vitronectina/antagonistas & inhibidores , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
6-[4-Amidinobenzoyl]amino]-tetralone-2-acetic acid is a potent antagonist of GPIIb-IIIa. Substitution in the meta position of the benzamidine, or replacement with a heteroaryl amidine was tolerated in this series. Use of an acyl-linked 4-alkyl piperidine as an arginine isostere also provided active compounds. Compounds from this series provided substantial systemic exposure in the rat following oral administration.
Asunto(s)
Acetatos/metabolismo , Amidinas/metabolismo , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Tetralonas , Adenosina Difosfato/farmacología , Animales , Arginina/química , Benzamidinas/química , Disponibilidad Biológica , Evaluación de Medicamentos , Ensayo de Inmunoadsorción Enzimática , Fibrinógeno/metabolismo , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Agregación Plaquetaria/efectos de los fármacos , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Profármacos/síntesis química , Profármacos/química , Profármacos/farmacocinética , Unión Proteica/efectos de los fármacos , Estructura Secundaria de Proteína , Ratas , EstereoisomerismoRESUMEN
Disubstituted isoquinolones 2 and 3 have affinity for GPIIb-IIIa and represent leads for further structural evaluation. Structure-activity studies centered on the bicyclic beta-turn mimic contained in these molecules indicated that this moiety could accommodate a variety of modifications. Specifically, monocyclic, 6, 5-bicyclic, and 6,7-bicyclic structures provide compounds with affinity for GPIIb-IIIa. Within the 6,6-series, isoquinoline, tetralin, tetralone, and benzopyran nuclei yield potent antagonists that are specific for GPIIb-IIIa. Attachment of the arginine isostere (benzamidine) to the supporting nucleus can be accomplished with an ether or amide linkage, although the latter enhances activity. Several compounds in this series provided measurable blood levels after oral dosing. Conversion of the acid moiety in these molecules to an ester generally provided compounds which gave greater systemic exposure after oral administration. Absolute bioavailabilities in the rat for the ethyl ester prodrug derivatives of the tetralin, tetralone, and benzopyran analogues of 3 were 28%, 23%, and 24%, respectively.