RESUMEN
Herein we report the discovery of a novel oxindole-based series of vasopressin 1b (V1b) receptor antagonists. Introducing a substituted piperazine moiety and optimizing the southern and the northern aromatic rings resulted in potent, selective and brain penetrant V1b receptor antagonists. Compound 9c was found to be efficacious in a rat model of anti-depressant activity (3â¯mg/kg, ip). Interestingly, both moderate terminal half-life and moderate bioavailability could be achieved despite sub-optimal microsomal stability.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacocinética , Animales , Antidepresivos/farmacocinética , Antidepresivos/farmacología , Disponibilidad Biológica , Encéfalo/metabolismo , Semivida , Humanos , Microsomas/metabolismo , Modelos Animales , Ratas , Relación Estructura-ActividadRESUMEN
Herein we report the discovery of a novel series of vasopressin 1b (V1b) receptor antagonists, starting from potent but metabolically labile oxindole SSR149415. Masking the proline N,N-dimethyl amide moiety as an oxazole and attaching a benzylic amine moiety to the northern phenyl ring resulted in potent and selective V1b receptor antagonists with improved metabolic stability and improved pharmacokinetic properties in rat. Compound 18c was found to be efficacious in a rat model of anti-depressant activity.
Asunto(s)
Antidepresivos/síntesis química , Antidepresivos/farmacocinética , Antagonistas de los Receptores de Hormonas Antidiuréticas , Indoles/síntesis química , Indoles/farmacocinética , Animales , Antidepresivos/química , Antidepresivos/farmacología , Modelos Animales de Enfermedad , Indoles/química , Indoles/farmacología , Estructura Molecular , Oxindoles , Unión Proteica/efectos de los fármacos , RatasRESUMEN
The industrial chemical 1,3-butadiene (BD) is a potent carcinogen in mice and a weak one in rats. This difference is generally related to species-specific burdens by the metabolites 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), and 3,4-epoxy-1,2-butanediol (EBD), which are all formed in the liver. Only limited data exist on BD metabolism in the rodent liver. Therefore, metabolism of BD, its epoxides, and the intermediate 3-butene-1,2-diol (B-diol) was studied in once-through perfused livers of male B6C3F1 mice and Sprague-Dawley rats. In BD perfusions, predominantly EB and B-diol were found (both species). DEB and EBD were additionally detected in mouse livers. Metabolism of BD showed saturation kinetics (both species). In EB perfusions, B-diol, EBD, and DEB were formed with B-diol being the major metabolite. Net formation of DEB was larger in mouse than in rat livers. In both species, hepatic clearance (Cl(H)) of EB was slightly smaller than the perfusion flow. In DEB perfusions, EBD was formed as a major metabolite. Cl(H) of DEB was 61% (mouse) and 73% (rat) of the perfusion flow. In the B-diol-perfused rat liver, EBD was formed as a minor metabolite. Cl(H) of B-diol was 53% (mouse) and 34% (rat) of the perfusion flow. In EBD-perfused rat livers, Cl(H) of EBD represented only 22% of the perfusion flow. There is evidence for qualitative species differences with regard to the enzymes involved in BD metabolism. The first quantitative findings in whole livers showing intrahepatic first-pass metabolism of BD and EB metabolites will improve the risk estimation of BD.