RESUMO
A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.
Assuntos
Indóis/química , Indóis/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Cristalografia por Raios X , Indazóis/química , Indazóis/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/química , Fosforilação , Relação Estrutura-AtividadeRESUMO
A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC(50)=16 and 66 nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation.
Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Triazóis/química , Triazóis/farmacologia , Animais , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Ratos , Relação Estrutura-Atividade , Triazóis/síntese químicaRESUMO
A novel series of highly selective JNK inhibitors based on the 4-quinolone scaffold was designed and synthesized. Structure based drug design was utilized to guide the compound design as well as improvements in the physicochemical properties of the series. Compound (13c) has an IC(50) of 62/170 nM for JNK1/2, excellent kinase selectivity and impressive efficacy in a rodent asthma model.
Assuntos
4-Quinolonas/farmacologia , Descoberta de Drogas , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , 4-Quinolonas/síntese química , 4-Quinolonas/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Here we report on the discovery of a series of maleimides which have high potency and good selectivity for GSK-3beta. The incorporation of polar groups afforded compounds with good bioavailability. The most potent compound 34 has an IC(50) of 0.6nM for GSK-3beta, over 100-fold selectivity against a panel of other kinases, and shows efficacy in rat osteoporosis models. The X-ray structure of GSK-3beta protein with 34 bound revealed the binding mode of the template and provided insights for future optimization opportunities.
Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Indóis/química , Maleimidas/química , Inibidores de Proteínas Quinases/química , Administração Oral , Animais , Sítios de Ligação , Cristalografia por Raios X , Modelos Animais de Doenças , Descoberta de Drogas , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Indóis/síntese química , Indóis/farmacocinética , Maleimidas/síntese química , Maleimidas/farmacocinética , Camundongos , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.