RESUMEN
A serendipitous discovery that the metalloprotease binding profile of a novel class of 2-carboxamide-3-hydroxamic acid piperidines could be significantly attenuated by the modification of the unexplored P1 substituent enabled the design and synthesis of a novel 2-carboxamide-1-hydroxamic acid cyclohexyl scaffold core that exhibited excellent HER-2 potency and unprecedented MMP-selectivity that we believe would not have been possible via conventional P1' perturbations.
Asunto(s)
Proteínas ADAM/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Antineoplásicos/síntesis química , Ácidos Hidroxámicos/síntesis química , Proteínas de la Membrana/metabolismo , Receptor ErbB-2/metabolismo , Proteína ADAM10 , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Diseño de Fármacos , Humanos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Metaloproteinasa 2 de la Matriz/metabolismo , Unión Proteica , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
A series of beta-sulfonamide piperidine hydroxamates were prepared and shown to be potent inhibitors of the human epidermal growth factor receptor-2 (HER-2) sheddase with excellent selectivity against MMP-1, -2, -3, and -9. This was achieved by exploiting subtle differences within the otherwise highly conserved S(1)(') binding pocket of the active sites within the metalloprotease family. In addition, it was discovered that the introduction of polarity to the P(1) and P(1)(') groups reduced the projected human clearance.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Metaloproteinasas de la Matriz/metabolismo , Piperidinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Sitios de Unión , Humanos , Metaloproteinasas de la Matriz/química , Piperidinas/química , Piperidinas/metabolismo , Receptor ErbB-2/químicaRESUMEN
In an effort to obtain a MMP selective and potent inhibitor of HER-2 sheddase (ADAM-10), the P1' group of a novel class of (6S,7S)-7-[(hydroxyamino)carbonyl]-6-carboxamide-5-azaspiro[2.5]octane-5-carboxylates was attenuated and the structure-activity relationships (SAR) will be discussed. In addition, it was discovered that unconventional perturbation of the P2' moiety could confer MMP selectivity, which was hypothesized to be a manifestation of the P2' group effecting global conformational changes.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácidos Hidroxámicos/química , Proteínas de la Membrana/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Receptor ErbB-2/antagonistas & inhibidores , Proteínas ADAM/metabolismo , Proteína ADAM10 , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Compuestos Aza/síntesis química , Compuestos Aza/química , Compuestos Aza/farmacología , Diseño de Fármacos , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Proteínas de la Membrana/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Receptor ErbB-2/metabolismo , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
The design, synthesis, evaluation, and identification of a novel class of (6S,7S)-N-hydroxy-6-carboxamide-5-azaspiro[2.5]octane-7-carboxamides as the first potent and selective inhibitors of human epidermal growth factor receptor-2 (HER-2) sheddase is described. Several compounds were identified that possess excellent pharmacodynamic and pharmacokinetic properties and were shown to decrease tumor size, cleaved HER-2 extracellular domain plasma levels, and potentiate the effects of the humanized anti-HER-2 monoclonal antibody (trastuzumab) in vivo in a HER-2 overexpressing cancer murine xenograft model.
Asunto(s)
Amidas/síntesis química , Antineoplásicos/síntesis química , Ácidos Hidroxámicos/síntesis química , Piperidinas/síntesis química , Receptor ErbB-2/antagonistas & inhibidores , Compuestos de Espiro/síntesis química , Administración Oral , Amidas/farmacocinética , Amidas/farmacología , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Humanos , Ácidos Hidroxámicos/farmacocinética , Ácidos Hidroxámicos/farmacología , Ratones , Conformación Molecular , Piperidinas/química , Piperidinas/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Trasplante Heterólogo , TrastuzumabRESUMEN
Liver transplantation (LT) was achieved for factor V Leiden-induced thrombophilia in a neonate with hepatic veno-occlusive disease. Initial LT was performed with a liver segment removed from a child with primary oxalosis. Four months later, a second, definitive LT was performed. The child remains well without recurrent thrombosis.