RESUMO
The SAR of a series of tri-substituted thiophene JNK3 inhibitors is described. By optimizing both the N-aryl acetamide region of the inhibitor and the 4-position of the thiophene we obtained single digit nanomolar compounds, such as 47, which demonstrated an in vivo effect on JNK activity when dosed orally in our kainic acid mouse model as measured by phospho-c-jun reduction.
Assuntos
Encéfalo/metabolismo , MAP Quinase Quinase 4/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Administração Oral , Desenho de Fármacos , Ligação de Hidrogênio , Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Relação Estrutura-AtividadeRESUMO
In this Letter, we describe the discovery of selective JNK2 and JNK3 inhibitors, such as 10, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs, p38α and ERK2. Substitution of the naphthalene ring affords an isoform selective JNK3 inhibitor, 30, with approximately 10-fold selectivity over both JNK1 and JNK2. A naphthalene ring penetrates deep into the selectivity pocket accounting for the differentiation amongst the kinases. Interestingly, the gatekeeper Met146 sulfide interacts with the naphthalene ring in a sulfur-π stacking interaction. Compound 38 ameliorates neurotoxicity induced by amyloid-ß in human cortical neurons. Lastly, we demonstrate how to install propitious in vitro CNS-like properties into these selective inhibitors.
Assuntos
Aminopiridinas/química , Proteína Quinase 10 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 9 Ativada por Mitógeno/antagonistas & inibidores , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/química , Inibidores de Proteínas Quinases/química , Triazinas/química , Aminopiridinas/farmacocinética , Aminopiridinas/uso terapêutico , Animais , Sítios de Ligação , Sistema Nervoso Central/metabolismo , Simulação por Computador , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-Atividade , Triazinas/farmacocinética , Triazinas/uso terapêuticoRESUMO
In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Αß by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30mpk BID for 2.5days.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Etilaminas/síntese química , Etilaminas/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Alquilação , Doença de Alzheimer , Animais , Encéfalo/metabolismo , Linhagem Celular , Cães , Desenho de Fármacos , Cobaias , Humanos , Indicadores e Reagentes , Inibidores de Proteases/farmacocinética , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
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.