RESUMO
A novel 2,6-naphthyridine was identified by high throughput screen (HTS) as a dual protein kinase C/D (PKC/PKD) inhibitor. PKD inhibition in the heart was proposed as a potential antihypertrophic mechanism with application as a heart failure therapy. As PKC was previously identified as the immediate upstream activator of PKD, PKD vs PKC selectivity was essential to understand the effect of PKD inhibition in models of cardiac hypertrophy and heart failure. The present study describes the modification of the HTS hit to a series of prototype pan-PKD inhibitors with routine 1000-fold PKD vs PKC selectivity. Example compounds inhibited PKD activity in vitro, in cells, and in vivo following oral administration. Their effects on heart morphology and function are discussed herein.
Assuntos
Aminopiridinas/síntese química , Naftiridinas/síntese química , Proteína Quinase C/antagonistas & inibidores , Transporte Ativo do Núcleo Celular , Administração Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Núcleo Celular/metabolismo , Histona Desacetilases/metabolismo , Isoenzimas/antagonistas & inibidores , Masculino , Modelos Moleculares , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Células Musculares/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Naftiridinas/farmacocinética , Naftiridinas/farmacologia , Fosforilação , Ligação Proteica , Ratos , Ratos Endogâmicos Dahl , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A systematic study of methyl ketone aldol additions under nonchelating conditions with alpha-alkoxy and alpha,beta-bisalkoxy aldehydes is described. Additions to aldehydes containing a single alpha-alkoxy stereocenter generally provide the product diastereomers in accord with the Cornforth/polar Felkin-Anh models for carbonyl addition. Vicinal asymmetric induction is sensitive to the aldehyde alpha-alkyl substituent, but is relatively insensitive to the nature of the alkoxy protecting group. Aldehyde pi-facial selectivity in additions to substrates containing an additional beta-alkoxy-substituted stereocenter exhibits a striking dependence on the relative configuration of the alpha- and beta-stereocenters. Aldehydes with the alpha- and beta-alkoxy substituents in an anti relationship in most cases exhibit good diastereoselectivity, while aldehydes with the alpha- and beta-alkoxy substituents in a syn relationship unexpectedly give product mixtures. A stereochemical model based on Cornforth-like transition-state arrangements is proposed.
