RESUMO
Screening of a library of diverse heterocyclic scaffolds identified substituted quinolines as inhibitors of the human proteasome. The heterocyclic library was prepared via a novel titanium-catalyzed multicomponent coupling reaction, which rendered a diverse set of isoxazoles, pyrimidines, pyrroles, pyrazoles and quinolines. SAR of the parent lead compound indicated that hydrophobic residues on the benzo-moiety significantly improved potency. Lead compound 25 inhibits the chymotryptic-like proteolytic activity of the proteasome (IC50 5.4µM), representing a new class of nonpeptidic, noncovalent proteasome inhibitors.
Assuntos
Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Quinolinas/farmacologia , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Estrutura Molecular , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
The proteasome has emerged as the primary target for the treatment of multiple myeloma. Unfortunately, nearly all patients develop resistance to competitive-type proteasome inhibitors such as bortezomib. Herein, we describe the optimization of noncompetitive proteasome inhibitors to yield derivatives that exhibit nanomolar potency (compound 49, IC50 130 nM) toward proteasome inhibition and overcome bortezomib resistance. These studies illustrate the feasibility of the development of noncompetitive proteasome inhibitors as additives and/or alternatives to competitive proteasome inhibitors.
Assuntos
Imidazolinas/síntese química , Inibidores de Proteassoma/síntese química , Ácidos Borônicos/farmacologia , Bortezomib , Linhagem Celular , Humanos , Imidazolinas/farmacologia , NF-kappa B/antagonistas & inibidores , Inibidores de Proteassoma/farmacologia , Pirazinas/farmacologiaRESUMO
The pathogenesis of rheumatoid arthritis is mainly driven by NF-κB-mediated production of cytokines, such as TNF-α. We report herein that the orally available imidazoline-based NF-κB inhibitor, TCH-013, was found to significantly reduce TNF-α signaling and attenuate collagen antibody induced arthritis in BALB/c mice.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Imidazóis/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Administração Oral , Animais , Artrite Reumatoide/induzido quimicamente , Colágeno , Relação Dose-Resposta a Droga , Imidazóis/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , NF-kappa B/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The pathogenesis of rheumatoid arthritis is mainly driven by NF-κB-mediated production of cytokines, such as TNF-α. We report herein that the orally available imidazoline-based NF-κB inhibitor, TCH-013, was found to significantly reduce TNF-α signaling and attenuate collagen antibody induced arthritis in BALB/c mice.
