RESUMEN
A series of spiro[chromane-2,4'-piperidine] derivatives based on a previously published lead benzyl spirocycle 1 and bearing various N-aryl and N-alkylaryl substituents on the piperidine ring were prepared as novel histone deacetylase (HDAC) inhibitors. The compounds were evaluated for their abilities to inhibit nuclear HDACs, their in vitro antiproliferative activities, and in vitro ADME profiles. Based on these activities, 4-fluorobenzyl and 2-phenylethyl spirocycles were selected for further characterization. In vivo pharmacokinetic (PK) studies showed that both compounds exhibit an overall lower clearance rate, an increased half-life, and higher AUCs after intravenous and oral administration than spiropiperidine 1 under the conditions used. The improved PK behavior of these two compounds also correlated with superior in vivo antitumor activity in an HCT-116 xenograft model.
Asunto(s)
Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Piperidinas/química , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Proteínas Sanguíneas/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos del Citocromo P-450 , Evaluación Preclínica de Medicamentos , Semivida , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/farmacocinética , Inyecciones Intravenosas , Tasa de Depuración Metabólica , Ratones , Ratones Desnudos , Estructura Molecular , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
New spiro[chromane-2,4'-piperidine] and spiro[benzofuran-2,4'-piperidine] hydroxamic acid derivatives as HDAC inhibitors have been identified by combining privileged structures with a hydroxamic acid moiety as zinc binding group. The compounds were evaluated for their ability to inhibit nuclear extract HDACs and for their in vitro antiproliferative activity on different tumor cell lines. This work resulted in the discovery of spirocycle 30d that shows good oral bioavailability and tumor growth inhibition in an HCT-116 murine xenograft model.
Asunto(s)
Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Inhibidores de Histona Desacetilasas/síntesis química , Humanos , Ácidos Hidroxámicos/síntesis química , Espectroscopía de Resonancia Magnética , Ratones , Estructura Molecular , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Lead optimization requires rapid bio-analytical turnover for the generation of early absorption, distribution, metabolism, excretion (ADME) and pharmacokinetics (PK) data maintaining a high quality level. Therefore, one of the major challenges in the bio-analytical field is to achieve faster and more sensitive quantification protocols. In the present communication, a comparison between HPLC and ultra performance liquid chromatography (UPLC) performances in terms of sensitivity and resolution is shown using a pharmakokinetic study and a metabolism study as models. The studies highlight the features of the new technology and the resulting impact in the PK throughput and in the characterization of isomeric metabolites using UPLC/MS/MS technique.