RESUMEN
Methylphenidate analogues, in which the carbomethoxy has been replaced by an alkyl group and with different phenyl substituents, have been synthesized and tested in monoamine transporter assays. As predicted from a pharmacophore model, most of the RR/SS diastereomers showed high potency as dopamine reuptake inhibitors. Analogues with a 4-chlorophenyl group and an unbranched initial alkyl atom had consistently enhanced selectivity for the dopamine transporter. The most potent compounds were those with a three- or four-carbon chain. The "inactive" RS/SR diastereomers showed substantial activity when the phenyl substituent was 3,4-dichloro. On a locomotor assay, one compound was found to have a slow onset and a long duration of action. The activity of these compounds provides additional evidence for a conformational/superposition model of methylphenidate with cocaine-like structures. A ketone analogue, obtained by hydrogenating a previously described vinylogous amide, had activity similar to that of methylphenidate.
Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Inhibidores de Captación de Dopamina/síntesis química , Metilfenidato/análogos & derivados , Metilfenidato/síntesis química , Animales , Línea Celular , Cristalografía por Rayos X , Inhibidores de Captación de Dopamina/farmacología , Humanos , Cetonas/síntesis química , Cetonas/farmacología , Masculino , Metilfenidato/farmacología , Ratones , Actividad Motora/efectos de los fármacos , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Ensayo de Unión Radioligante , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation cascade. To investigate the potential of FXIa inhibitors as safe anticoagulants, a series of potent, selective peptidomimetic inhibitors of FXIa were designed and synthesized. Some of these inhibitors showed low nanomolar FXIa inhibitory activity with >1000-fold FXa selectivity and >100-fold thrombin selectivity. The X-ray structure of one of these inhibitors, 36, demonstrates its unique binding interactions with FXIa. Compound 32 caused a doubling of the activated partial thromboplastin time in human plasma at 2.4 microM and was efficacious in a rat model of venous thrombosis. These data suggest that factor XIa plays a significant role in venous thrombosis and may be a suitable target for the development of antithrombotic therapy.
Asunto(s)
Anticoagulantes/farmacología , Diseño de Fármacos , Factor XIa/antagonistas & inhibidores , Inhibidores del Factor Xa , Fragmentos de Péptidos/síntesis química , Inhibidores de Serina Proteinasa/farmacología , Animales , Anticoagulantes/síntesis química , Anticoagulantes/química , Sitios de Unión , Cristalografía por Rayos X , Humanos , Concentración 50 Inhibidora , Masculino , Estructura Molecular , Tiempo de Tromboplastina Parcial , Fragmentos de Péptidos/química , Fragmentos de Péptidos/farmacología , Unión Proteica , Conformación Proteica , Ratas , Ratas Sprague-Dawley , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/química , Relación Estructura-Actividad , Trombina/antagonistas & inhibidores , Trombosis de la Vena/tratamiento farmacológicoRESUMEN
Using an alpha-ketothiazole arginine moiety as a key recognition element, a series of small peptidomimetic molecules was designed and synthesized, and their co-crystal structures with factor XIa were studied in an effort to develop smaller, less peptidic inhibitors as antithrombotic agents.