RESUMO
The indolyl-naphthyl maleimide 7 is a potent inhibitor of the classical PKC isotypes α,ß and shows excellent selectivity over the novel PKC isotypes δ,ε,η,θ and other kinases belonging to the AGC family. The SAR around 7 as well as the physico-chemical characteristics of selected derivatives and their activity in T and B cell activation and proliferation assays are discussed.
Assuntos
Linfócitos B/efeitos dos fármacos , Maleimidas/química , Maleimidas/farmacologia , Proteína Quinase C beta/antagonistas & inibidores , Proteína Quinase C-alfa/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Linfócitos B/citologia , Linfócitos B/metabolismo , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Humanos , Indóis/química , Concentração Inibidora 50 , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Maleimidas/síntese química , Simulação de Acoplamento Molecular , Naftóis/química , Ligação Proteica , Proteína Quinase C beta/metabolismo , Proteína Quinase C-alfa/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Linfócitos T/citologia , Linfócitos T/metabolismoRESUMO
A novel class of selective inhibitors of ROCK1 and ROCK2 has been identified by structural based drug design. PK/PD experiments using a set of highly selective Rho kinase inhibitors suggest that systemic Rho kinase inhibition is linked to a reversible reduction in lymphocyte counts. These results led to the consideration of topical delivery of these molecules, and to the identification of a lead molecule 7 which shows promising PK and PD in a murine model of pulmonary hypertension after intra-tracheal dosing.
Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Animais , Cristalografia por Raios X , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismoRESUMO
We describe two series of Syk inhibitors which potently abrogate Syk kinase function in enzymatic assays, cellular assays and in primary cells in the presence of blood. Introduction of a 7-aminoindole substituent led to derivatives with good kinase selectivity and little or no hERG channel inhibition (3b, 10c).
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/sangue , Humanos , Indóis/sangue , Indóis/química , Indóis/farmacologia , Inibidores de Proteínas Quinases/química , Quinase SykRESUMO
The present study describes a novel series of ATP-competitive PKC inhibitors based on the 2,6-naphthyridine template. Example compounds potently inhibit the novel Protein Kinase C (PKC) isotypes δ, ε, η, θ (in particular PKCε/η, and display a 10-100-fold selectivity over the classical PKC isotypes. The prototype compound 11 was found to inhibit PKCθ-dependent pathways in vitro and in vivo. In vitro, a-CD3/a-CD28-induced lymphocyte proliferation could be effectively blocked in 10% rat whole blood. In mice, 11 dose-dependently inhibited Staphylococcus aureus enterotoxin B-triggered IL-2 serum levels after oral dosing.
Assuntos
Naftiridinas/química , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Administração Oral , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Enterotoxinas/toxicidade , Interleucina-2/sangue , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Camundongos , Naftiridinas/síntese química , Naftiridinas/farmacocinética , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Terciária de Proteína , Ratos , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
We describe the discovery of selective and potent Syk inhibitor 11, which exhibited favorable PK profiles in rat and dog and was found to be active in a collagen-induced arthritis model in rats. Compound 11 was selected for further profiling, but, unfortunately, in GLP toxicological studies it showed liver findings in rat and dog. Nevertheless, 11 could become a valuable tool compound to investigate the rich biology of Syk in vitro and in vivo.
Assuntos
Artrite Experimental/tratamento farmacológico , Descoberta de Drogas , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Artrite Experimental/induzido quimicamente , Colágeno , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Conformação Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/sangue , Proteínas Tirosina Quinases/metabolismo , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , Quinase SykRESUMO
Three novel aspects emerge for the reaction of [5]metacyclophane (1) with the (intermediate) phenylphosphinidene complex 2 to give the 7-phosphanorbornadiene 3. It is the first 1,4-addition of a phosphinidene complex to an unsaturated system, the first addition of a phosphinidene complex to a benzene ring, and the first [4+1] cycloaddition to an aromatic compound.
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
The synthesis and biological evaluation of potent and selective PKD inhibitors are described herein. The compounds described in the present study selectively inhibit PKD among other putative HDAC kinases. The PKD inhibitors of the present study blunt phosphorylation and subsequent nuclear export of HDAC4/5 in response to diverse agonists. These compounds further establish the central role of PKD as an HDAC4/5 kinase and enhance the current understanding of cardiac myocyte signal transduction. The in vivo efficacy of a representative example compound on heart morphology is reported herein.