RESUMEN
From high throughput screening, we discovered compound 1, the prototype for a series of disubstituted thiophene inhibitors of JNK which is selective towards closely related MAP kinases p38 and Erk2. Herein we describe the evolution of these compounds to a novel class of thiophene and thiazole JNK inhibitors that retain favorable solubility, permeability, and P-gp properties for development as CNS agents for treatment of neurodegeneration. Compound 61 demonstrated JNK3 IC(50)=77 nM and retained the excellent broad kinase selectivity observed for the series.
Asunto(s)
Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Quinolinas/síntesis química , Tiazoles/química , Tiofenos/química , Animales , Diseño de Fármacos , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Ratones , Microsomas Hepáticos/metabolismo , Proteína Quinasa 10 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 10 Activada por Mitógenos/metabolismo , Proteína Quinasa 8 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Quinolinas/química , Quinolinas/farmacología , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacología , Tiofenos/síntesis química , Tiofenos/farmacologíaRESUMEN
Herein we describe further evolution of hydroxyethylamine inhibitors of BACE-1 with enhanced permeability characteristics necessary for CNS penetration. Variation at the P2' position of the inhibitor with more polar substituents led to compounds 19 and 32, which retained the potency of more lipophilic analog 1 but with much higher observed passive permeability in MDCK cellular assay.
Asunto(s)
Acetamidas/química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Butanoles/química , Ciclohexilaminas/química , Inhibidores de Proteasas/química , Acetamidas/síntesis química , Acetamidas/farmacocinética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Sitios de Unión , Butanoles/síntesis química , Butanoles/farmacocinética , Permeabilidad de la Membrana Celular/efectos de los fármacos , Cristalografía por Rayos X , Ciclohexilaminas/síntesis química , Ciclohexilaminas/farmacocinética , Humanos , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Relación Estructura-ActividadRESUMEN
The hydroxyethylene (HE) transition state isostere was developed as a scaffold to provide potent, small molecule inhibitors of human beta-secretase (BACE). The previous work on the statine series proved critical to the discovery of HE structure-activity relationships. Compound 20 with the N-terminal isophthalamide proved to be the most potent HE inhibitor (IC(50) = 30 nM) toward BACE. Unlike the statine series, we identified HE inhibitors without carboxylic acids on the C terminus, leading to enhanced cell penetration and making them attractive candidates for further drug development in Alzheimer's disease.
Asunto(s)
Amidas/síntesis química , Ácido Aspártico Endopeptidasas/química , Dipéptidos/química , Etilenos/síntesis química , Ácidos Ftálicos/síntesis química , Inhibidores de Proteasas/síntesis química , Amidas/química , Secretasas de la Proteína Precursora del Amiloide , Diseño de Fármacos , Endopeptidasas , Etilenos/química , Humanos , Modelos Moleculares , Imitación Molecular , Ácidos Ftálicos/química , Inhibidores de Proteasas/química , Relación Estructura-ActividadRESUMEN
We describe the development of statine-based peptidomimetic inhibitors of human beta-secretase (BACE). The conversion of the peptide inhibitor 1 into cell-permeable peptidomimetic inhibitors of BACE was achieved through an iterative strategy of conceptually subdividing 1 into three regions: an N-terminal portion, a central statine-containing core, and a C-terminus. Replacement of the amino acid residues of 1 with moieties with less peptidic character was done with retention of BACE enzyme inhibitory activity. This approach led to the identification of the cell-permeable BACE inhibitor 38 that demonstrated BACE-mechanism-selective inhibition of Abeta secretion in human embryonic kidney cells.
