RESUMEN
A novel series of 1,2-disubstituted indole, azaindole and benzimidazole derivatives possessing an amine moiety was identified as thrombin inhibitors. An indole with basic diamine moieties (12a) was the most potent thrombin inhibitor in the series with Kass= 197 x 10(6) L/mol.
Asunto(s)
Anticoagulantes/síntesis química , Compuestos Aza/síntesis química , Bencimidazoles/síntesis química , Indoles/síntesis química , Trombina/antagonistas & inhibidores , Aminas/síntesis química , Aminas/química , Aminas/farmacología , Anticoagulantes/química , Anticoagulantes/farmacología , Compuestos Aza/química , Compuestos Aza/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Diseño de Fármacos , Indoles/química , Indoles/farmacología , Cinética , Estructura Molecular , 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.
Asunto(s)
Benzopiranos/síntesis química , Isoquinolinas/síntesis química , Oligopéptidos/química , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Tetrahidronaftalenos/síntesis química , Administración Oral , Animales , Benzopiranos/química , Benzopiranos/farmacocinética , Benzopiranos/farmacología , Unión Competitiva , Disponibilidad Biológica , Ensayo de Inmunoadsorción Enzimática , Cobayas , Humanos , Isoquinolinas/química , Isoquinolinas/farmacocinética , Isoquinolinas/farmacología , Imitación Molecular , Agregación Plaquetaria/efectos de los fármacos , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Estructura Secundaria de Proteína , Ratas , Relación Estructura-Actividad , Tetrahidronaftalenos/química , Tetrahidronaftalenos/farmacocinética , Tetrahidronaftalenos/farmacologíaRESUMEN
Cyclic heptapeptide 1, which contains an Arg-Gly-Asp sequence, has good affinity for the platelet receptor GPIIb-IIIa and was chosen for study by 1H NMR techniques. The key RGD sequence of this molecule was found to reside in a conformationally defined type II' Gly-Asp beta-turn, and this information was used in the design of simple non-peptide RGD mimics. Disubstituted isoquinolones, bearing an acidic side chain at position 2 and a basic side chain at position 6, were prepared and were found to have modest affinity for GPIIb-IIIa. Systematic modification of the basic residue contained in these molecules yielded compounds with high affinity for GPIIb-IIIa.
