RESUMO
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.
Assuntos
Indazóis/síntese química , Indóis/síntese química , Maleimidas/síntese química , Proteína Quinase C/antagonistas & inibidores , Animais , Linhagem Celular , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/química , Glicogênio Sintase Quinase 3 beta , Cobaias , Humanos , Indazóis/farmacologia , Indazóis/toxicidade , Indóis/farmacologia , Indóis/toxicidade , Interleucina-8/metabolismo , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Síndrome do QT Longo/induzido quimicamente , Maleimidas/farmacologia , Maleimidas/toxicidade , Modelos Moleculares , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Proteína Quinase C/química , Proteína Quinase C beta , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Indóis/síntese química , Maleimidas/síntese química , Proteína Quinase C/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular , Ciclização , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta , Humanos , Indóis/farmacologia , Concentração Inibidora 50 , Isoenzimas/síntese química , Isoenzimas/farmacologia , Maleimidas/farmacologia , Proteína Quinase C beta , Relação Estrutura-AtividadeRESUMO
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.
