RESUMEN
A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.
Asunto(s)
Antineoplásicos/síntesis química , Formamidas/síntesis química , Hidroxilaminas/síntesis química , Metaloendopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Disponibilidad Biológica , Línea Celular , Formamidas/química , Formamidas/farmacocinética , Formamidas/farmacología , Hidroxilaminas/química , Hidroxilaminas/farmacocinética , Hidroxilaminas/farmacología , Macaca fascicularis , Inhibidores de la Metaloproteinasa de la Matriz , Ratones , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Trifluoromethyl ketones were found to be inhibitors of histone deacetylases (HDACs). Optimization of this series led to the identification of submicromolar inhibitors such as 20 that demonstrated antiproliferative effects against the HT1080 and MDA 435 cell lines.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Cetonas/química , Cetonas/farmacología , Acetilación , Western Blotting , Neoplasias de la Mama/metabolismo , Ciclo Celular/efectos de los fármacos , Fibrosarcoma/metabolismo , Histonas/metabolismo , Humanos , Hidrocarburos Fluorados/química , Hidrocarburos Fluorados/farmacología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A series of succinimide hydroxamic acids was prepared and evaluated in vitro for HDAC inhibition and tumor cell antiproliferation. While the original macrocyclic analogue 6 was quite potent in both assays, several appropriately substituted non-macrocyclic succinimides, such as 23, were equipotent.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Succinimidas/síntesis química , Succinimidas/farmacología , Aminoácidos/química , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Ácidos Hidroxámicos/metabolismo , Indicadores y Reactivos , Células K562 , Conformación Molecular , Relación Estructura-Actividad , Succinimidas/metabolismo , Células Tumorales CultivadasRESUMEN
Alpha-keto ester and amides were found to be potent inhibitors of histone deacetylase. Nanomolar inhibitors against the isolated enzyme and sub-micromolar inhibitors of cellular proliferation were obtained. The alpha-keto amide 30 also exhibited significant anti-tumor effects in an in vivo tumor model.