RESUMEN
The development and application of high-load, recyclable magnetic Co/C hybrid ROMP-derived benzenesulfonyl chloride and analogues is reported. The regeneration and utility of these reagents in the methylation/alkylation of various carboxylic acids is demonstrated via efficient retrieval of the magnetic reagent with a neodymium magnet. Additional reactions employing the analogue sulfonic acid and in situ generated magnetic benzenesulfonyl azide are also reported.
Asunto(s)
Carbono/química , Cobalto/química , Nanopartículas de Magnetita/química , Sulfonas/síntesis química , Alquilación , Ácidos Carboxílicos/química , Indicadores y Reactivos , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.
Asunto(s)
Antineoplásicos/farmacología , Janus Quinasa 2/antagonistas & inhibidores , Neoplasias Experimentales/tratamiento farmacológico , Prolina/análogos & derivados , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Perros , Relación Dosis-Respuesta a Droga , Haplorrinos , Ensayos Analíticos de Alto Rendimiento , Janus Quinasa 2/metabolismo , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/patología , Prolina/administración & dosificación , Prolina/química , Prolina/farmacología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Ratas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinonas/química , Pirimidinonas/farmacocinética , Animales , Sitios de Unión , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Simulación por Computador , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Pirimidinonas/uso terapéutico , Ratas , Relación Estructura-Actividad , Trasplante Heterólogo , Regulación hacia ArribaRESUMEN
A series of substituted benzofuropyrimidinones with pan-PIM activities and excellent selectivity against a panel of diverse kinases is described. Initial exploration identified aryl benzofuropyrimidinones that were potent, but had cell permeability limitation. Using X-ray crystal structures of the bound PIM-1 complexes with 3, 5m, and 6d, we were able to guide the SAR and identify the alkyl benzofuropyrimidinone (6l) with good PIM potencies, permeability, and oral exposure.