RESUMEN
Novel indolylindazolylmaleimides were synthesized and examined for kinase inhibition. We identified low-nanomolar inhibitors of PKC-beta with good to excellent selectivity vs other PKC isozymes and GSK-3beta. In a cell-based functional assay, 8f and 8i effectively blocked IL-8 release induced by PKC-betaII (IC(50) = 20-25 nM). In cardiovascular safety assessment, representative lead compounds bound to the hERG channel with high affinity, potently inhibited ion current in a patch-clamp experiment, and caused a dose-dependent increase of QT(c) in guinea pigs.
Asunto(s)
Indazoles/síntesis química , Indoles/síntesis química , Maleimidas/síntesis química , Proteína Quinasa C/antagonistas & inhibidores , Animales , Línea Celular , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/química , Glucógeno Sintasa Quinasa 3 beta , Cobayas , Humanos , Indazoles/farmacología , Indazoles/toxicidad , Indoles/farmacología , Indoles/toxicidad , Interleucina-8/metabolismo , Isoenzimas/antagonistas & inhibidores , Isoenzimas/química , Síndrome de QT Prolongado/inducido químicamente , Maleimidas/farmacología , Maleimidas/toxicidad , Modelos Moleculares , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/química , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio con Entrada de Voltaje/efectos de los fármacos , Canales de Potasio con Entrada de Voltaje/metabolismo , Proteína Quinasa C/química , Proteína Quinasa C beta , Relación Estructura-ActividadRESUMEN
Efficient methods were developed to synthesize a novel series of macrocyclic bisindolylmaleimides containing linkers with multiple heteroatoms. Potent inhibitors (single digit nanomolar IC(50)) for PKC-beta and GSK-3beta were identified, and compounds showed good selectivity over PKC-alpha, -gamma, -delta, -epsilon, and -zeta. Representative compound 5a also had high selectivity in a screening panel of 10 other protein kinases. In cell-based functional assays, several compounds effectively blocked interleukin-8 release induced by PKC-betaII and increased glycogen synthase activity by inhibiting GSK-3beta.
Asunto(s)
Indoles/síntesis química , Maleimidas/síntesis química , Proteína Quinasa C/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular , Ciclización , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta , Humanos , Indoles/farmacología , Concentración 50 Inhibidora , Isoenzimas/síntesis química , Isoenzimas/farmacología , Maleimidas/farmacología , Proteína Quinasa C beta , Relación Estructura-ActividadRESUMEN
A new generation of indole-based peptide mimetics, bearing a basic amine at the C-terminus, was developed by the agency of two complementary, multistep, trityl resin-based approaches. Thus, we obtained several high-affinity thrombin receptor (PAR-1) ligands, such as 32 and 34. Compounds 32 and 34 were found to bind to PAR-1 with excellent affinity (IC(50)=25 and 35 nM, respectively) and to effectively block platelet aggregation induced by SFLLRN-NH(2) (TRAP-6) and alpha-thrombin.