RESUMEN
Novel dihydropyrrolopyrazole-substituted benzimidazoles were synthesized and evaluated in vitro as inhibitors of transforming growth factor-beta type I receptor (TGF-beta RI), TGF-beta RII, and mixed lineage kinase-7 (MLK-7). These compounds were found to be potent TGF-beta RI inhibitors and selective versus TGF-beta RII and MLK-7 kinases. Benzimidazole derivative 8b was active in an in vivo target (TGF-beta RI) inhibition assay.
Asunto(s)
Bencimidazoles/síntesis química , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/síntesis química , Pirroles/síntesis química , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Animales , Bencimidazoles/química , Bencimidazoles/farmacología , Células Cultivadas , Humanos , Ratones , Ratones Desnudos , Visón , Estructura Terciaria de Proteína , Pirazoles/química , Pirazoles/farmacología , Pirroles/química , Pirroles/farmacología , Receptor Tipo I de Factor de Crecimiento Transformador beta , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Glycogen synthase kinase-3 (GSK3) is involved in signaling from the insulin receptor. Inhibitors of GSK3 are expected to effect lowering of plasma glucose similar to insulin, making GSK3 an attractive target for the treatment of type 2 diabetes. Herein we report the discovery of a series of potent and selective GSK3 inhibitors. Compounds 7-12 show oral activity in an in vivo model of type II diabetes, and 9 and 12 have desirable PK properties.
Asunto(s)
Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Imidazoles/síntesis química , Piridinas/síntesis química , Pirroles/síntesis química , Administración Oral , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Glucógeno Sintasa Quinasa 3 beta , Humanos , Imidazoles/farmacocinética , Imidazoles/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Ratas ZuckerRESUMEN
Many 3-aryl-4-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl)maleimides exhibit potent GSK3 inhibitory activity (<100 nM IC(50)), although few show significant selectivity (>100x) versus CDK2, CDK4, or PKCbetaII. However, combining 3-(imidazo[1,2-a]pyridin-3-yl), 3-(pyrazolo[1,5-a]pyridin-3-yl) or aza-analogs with a 4-(2-acyl-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl)) group on the maleimide resulted in very potent inhibitors of GSK3 (=5 nM) with >160 to >10,000-fold selectivity versus CDK2/4 and PKCbetaII. These compounds also inhibited tau phosphorylation in cells and were effective in lowering plasma glucose in a rat model of type 2 diabetes (ZDF rat).
Asunto(s)
Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Maleimidas/síntesis química , Animales , Glucemia/efectos de los fármacos , Línea Celular , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Modelos Animales de Enfermedad , Humanos , Concentración 50 Inhibidora , Maleimidas/farmacología , Fosforilación/efectos de los fármacos , Ratas , Relación Estructura-Actividad , Proteínas tau/metabolismoRESUMEN
A novel series of 7-amino 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolines was synthesized and their TbetaR-1 inhibitory, p38 MAPK inhibitory, and TbetaR-1-dependent cellular activity were evaluated. Compound 5a was found to be a highly potent in the enzyme assay and TbetaR-1-dependent cellular assays. In addition, dimer (4g), with a urea linker, shows a similar enzyme and cellular activity despite a bulky substitution.
Asunto(s)
Receptores de Activinas Tipo I/antagonistas & inhibidores , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Células Cultivadas , Dimerización , Humanos , Concentración 50 Inhibidora , Proteínas Serina-Treonina Quinasas , Estructura Terciaria de Proteína , Pirazoles/síntesis química , Pirazoles/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Receptor Tipo I de Factor de Crecimiento Transformador beta , Relación Estructura-Actividad , Urea/química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
We have expanded our previously reported series of pyrazole-based inhibitors of the TGF-beta type I receptor kinase domain (TbetaR-I) to now include new 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole analogues. Limited examination of the SAR of this new series in both enzyme and cell based in vitro assays has revealed selectivity differences with respect to p38 MAP kinase (p38 MAPK) depending on the nature of the 'warhead' group on the dihydropyrrolopyrazole ring. As with our original pyrazole series, phenyl substituents tended to show greater selectivity against p38 MAPK than those comprised of the quinoline-4-yl moiety. We have also achieved co-crystallization and X-ray analysis of compounds 3 and 15, two potent examples of this new series, with the TbetaR-I receptor kinase domain.