RESUMEN
γ-Secretase modulators (GSMs) are potentially disease-modifying treatments for Alzheimer's disease. They selectively lower pathogenic Aß42 levels by shifting the enzyme cleavage sites without inhibiting γ-secretase activity, possibly avoiding known adverse effects observed with complete inhibition of the enzyme complex. A cell-based HTS effort identified the sulfonamide 1 as a GSM lead. Lead optimization studies identified compound 25 with improved cell potency, PKDM properties, and it lowered Aß42 levels in the cerebrospinal fluid (CSF) of Sprague-Dawley rats following oral administration. Further optimization of 25 to improve cellular potency is described.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Amidas/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Picolinas/farmacología , Enfermedad de Alzheimer/enzimología , Amidas/química , Animales , Células HEK293 , Humanos , Picolinas/química , Ratas , Ratas Sprague-DawleyRESUMEN
The discovery and optimization of a novel series of aminoisoquinolines as potent, selective, and efficacious inhibitors of the mutant B-Raf pathway is presented. The N-linked pyridylpyrimidine benzamide 2 was identified as a potent, modestly selective inhibitor of the B-Raf enzyme. Replacement of the benzamide with an aminoisoquinoline core significantly improved kinase selectivity and imparted favorable pharmacokinetic properties, leading to the identification of 1 as a potent antitumor agent in xenograft models.
Asunto(s)
Isoquinolinas/farmacología , Isoquinolinas/farmacocinética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas Mutantes/antagonistas & inhibidores , Mutación , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Descubrimiento de Drogas , Humanos , Isoquinolinas/administración & dosificación , Isoquinolinas/síntesis química , Masculino , Ratones , Modelos Moleculares , Conformación Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/química , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Ratas , Especificidad por SustratoRESUMEN
A series of 8-anilinoimidazo[4,5-g]quinoline-7-carbonitriles was synthesized and evaluated as Src kinase inhibitors. Several aniline substituents were surveyed, as well as water-solubilizing groups at the C-2 and N-3 positions. Potent Src inhibitors were identified, with N-3 providing the best position for an additional water-solubilizing group.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Nitrilos/síntesis química , Nitrilos/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Familia-src Quinasas/antagonistas & inhibidores , Fenómenos Químicos , Química Física , Indicadores y Reactivos , Solubilidad , Relación Estructura-ActividadRESUMEN
A series of substituted 4-anilino-7-phenyl-3-quinolinecarbonitriles has been prepared as Src kinase inhibitors. Optimal activity is observed with compounds that have basic amines attached via the para position of the 7-phenyl ring, and a hydrogen atom at the C-6 position. The best compounds are low nanomolar inhibitors of Src kinase, and have potent activity against Src-transformed fibroblast cells.