RESUMEN
A series of (3R,4R)-pyrrolidine-3,4-dicarboxylic acid amides was investigated with respect to their factor Xa inhibitory activity, selectivity, pharmacokinetic properties, and ex vivo antithrombotic activity. The clinical candidate from this series, R1663, exhibits excellent selectivity against a panel of serine proteases and good pharmacokinetic properties in rats and monkeys. A Phase I clinical study with R1663 has been finalized.
Asunto(s)
Inhibidores del Factor Xa , Pirrolidinas/farmacología , Pirrolidinas/químicaRESUMEN
Starting from a hit identified by focused screening, 3-aminopyrrolidine factor Xa inhibitors were designed. The binding mode as determined by X-ray structural analysis as well as the pharmacokinetic behaviour of selected compounds is discussed.
Asunto(s)
Aminoquinolinas/farmacología , Antitrombina III/farmacología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Factor Xa/metabolismo , Aminoquinolinas/química , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacocinética , Antitrombina III/química , Antitrombina III/metabolismo , Antitrombina III/farmacocinética , Cristalografía por Rayos X , Factor Xa/química , Humanos , Modelos Moleculares , Conformación MolecularRESUMEN
The discovery of a highly potent and selective tissue factor/factor VIIa inhibitor is described. Upon oral administration of its double prodrug in the guinea pig, a dose-dependent antithrombotic effect is observed in an established model of arterial thrombosis without prolonging bleeding time. The pharmacodynamic properties of this selective inhibitor are compared to the behaviour of a mixed factor VIIa/factor Xa inhibitor.
Asunto(s)
Anticoagulantes/síntesis química , Anticoagulantes/farmacología , Inhibidores de Factor de Coagulación Sanguínea/síntesis química , Inhibidores de Factor de Coagulación Sanguínea/farmacología , Factor VIIa/antagonistas & inhibidores , Tromboplastina/antagonistas & inhibidores , Administración Oral , Animales , Tiempo de Sangría , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Cobayas , Humanos , Modelos Moleculares , Estructura Molecular , Profármacos/síntesis química , Profármacos/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Trombosis/tratamiento farmacológico , Trombosis/prevención & controlRESUMEN
Traditional setups for in situ MR investigation of skeletal muscle function in animals use invasive systems for muscle stimulation and force measurement. These systems require surgical preparation and therefore exclude repetitive investigations on the same animal. This article describes a new experimental setup allowing strictly noninvasive MR investigations of muscle function in contracting rat gastrocnemius muscle using 1H-MR imaging and 31P-MR spectroscopy. The novelty of this setup is the integration of two noninvasive systems allowing muscle contraction by transcutaneous stimulation and force measurement with a dedicated ergometer. Muscle function was investigated in 20 rats (275-300 g) through a fatiguing stimulation protocol, either with this noninvasive setup (n = 10) or with a traditional MR setup (n = 10). T2-weighted images demonstrated that transcutaneous stimulation activated mainly the gastrocnemius muscle. Moreover, the changes in force development and in energy metabolism obtained with the noninvasive setup were qualitatively and quantitatively similar to those obtained with the traditional setup. This noninvasive setup is thus suitable for investigating skeletal muscle function in situ. It offers the possibility to repeat investigations in the same animal, avoiding individual variability and enabling longitudinal follow-up studies. This opens up new perspectives in various research areas including pharmaceutical research.
Asunto(s)
Metabolismo Energético/fisiología , Interpretación de Imagen Asistida por Computador/métodos , Contracción Isométrica/fisiología , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/métodos , Músculo Esquelético/anatomía & histología , Músculo Esquelético/fisiología , Adenosina Trifosfato/metabolismo , Animales , Diseño de Equipo , Análisis de Falla de Equipo , Miembro Posterior/anatomía & histología , Miembro Posterior/fisiología , Masculino , Fosfocreatina/metabolismo , Isótopos de Fósforo , Proyectos Piloto , Protones , Ratas , Ratas Wistar , Estrés Mecánico , TransductoresRESUMEN
New orally active non-terpenoic inhibitors of human 2,3-oxidosqualene cyclase (hOSC) are reported. The starting point for the optimization process was a set of compounds derived from a fungicide project, which in addition to showing high affinity for OSC from Candida albicans showed also high affinity for human OSC. Common structural elements of these inhibitors are an amine residue and an electrophilic carbonyl C atom embedded in a benzophenone system, which are at a distance of about 10.7 A. Considering that the keto moiety is in a potentially labile position, modifications of the substitution pattern at the benzophenone as well as annelated heteroaryl systems were explored. Our approach combined testing of the compounds first for increased binding affinity and for increased stability in vitro. Most promising compounds were then evaluated for their efficacy in lowering plasma total cholesterol (TC) and plasma low-density lipoprotein cholesterol (LDL-C) in hyperlipidemic hamsters. In this respect, the most promising compounds are the benzophenone derivative 1.fumarate and the benzo[d]isothiazol 24.fumarate, which lowered TC by 40% and 33%, respectively.