RESUMO
The 7-alkene-3-quinolinecarbonitrile 20, a potent inhibitor of Src enzymatic and cellular activity with IC(50) values of 2.1 and 58 nM, respectively, had comparable efficacy to bosutinib in a colon tumor xenograft study.
Assuntos
Antineoplásicos/química , Inibidores de Proteínas Quinases/química , Quinolinas/química , Quinases da Família src/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Humanos , Camundongos , Camundongos Nus , Microssomos/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/metabolismoRESUMO
Src kinase signaling has been implicated in multiple mechanisms of ischemic injury, including vascular endothelial growth factor (VEGF)-mediated vascular permeability that leads to vasogenic edema, a major clinical complication in stroke and brain trauma. Here we report the effects of two novel Src kinase inhibitors, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile (SKI-606) and 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[4-(4-methypiperazin-1-yl)but-1-ynyl]-3-quinolinecarbonitrile (SKS-927), on ischemia-induced brain infarction and short- and long-term neurological deficits. Two well established transient [transient middle cerebral artery occlusion (tMCAO)] and permanent [permanent middle cerebral artery occlusion (pMCAO)] focal ischemia models in the rat were used with drug treatments initiated up to 6 h after onset of stroke to mimic the clinical scenario. Brain penetration of Src inhibitors, their effect on blood-brain barrier integrity and VEGF signaling in human endothelial cells were also evaluated. Our results demonstrate that both agents potently block VEGF-mediated signaling in human endothelial cells, penetrate rat brain upon systemic administration, and inhibit postischemic Src activation and vascular leakage. Treatment with SKI-606 or SKS-927 (at the doses of 3-30 mg/kg i.v.) resulted in a dose-dependent reduction in infarct volume and robust protection from neurological impairments even when the therapy was initiated up to 4- to 6-h after tMCAO. Src blockade after pMCAO resulted in accelerated improvement in recovery from motor, sensory, and reflex deficits during a long-term (3 weeks) testing period poststroke. These data demonstrate that the novel Src kinase inhibitors provide effective treatment against ischemic conditions within a clinically relevant therapeutic window and may constitute a viable therapy for acute stroke.
Assuntos
Compostos de Anilina/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Nitrilas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Quinases da Família src/antagonistas & inibidores , Compostos de Anilina/administração & dosagem , Compostos de Anilina/química , Compostos de Anilina/farmacocinética , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/enzimologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/metabolismo , Isquemia Encefálica/enzimologia , Permeabilidade Capilar , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/enzimologia , Citometria de Fluxo , Humanos , Injeções Intravenosas , Masculino , Estrutura Molecular , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Testes Neuropsicológicos , Nitrilas/administração & dosagem , Nitrilas/química , Nitrilas/farmacocinética , Piperazinas/administração & dosagem , Piperazinas/química , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/administração & dosagem , Quinolinas/química , Quinolinas/farmacocinética , Ratos , Ratos Wistar , Fatores de TempoRESUMO
The thieno[2,3-b]pyridine-5-carbonitrile with a 5-indolylamine at C-4 and a phenyl group at C-2 had a moderate activity against PKCtheta. Optimization of the groups at C-4 and C-2 led to analog 29, which has an IC(50) value of 7.5nM for the inhibition of PKCtheta.
Assuntos
Antineoplásicos/farmacologia , Isoenzimas/antagonistas & inibidores , Nitrilas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Tiofenos/farmacologia , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/patologia , Concentração Inibidora 50 , Camundongos , Camundongos Knockout , Modelos Químicos , Nitrilas/síntese química , Inibidores de Proteínas Quinases/síntese química , Piridinas/síntese química , Ratos , Relação Estrutura-Atividade , Tiofenos/síntese químicaRESUMO
Of a series of 7-ethynyl-3-quinolinecarbonitriles, the most potent Src inhibitory activity was observed with 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[4-(4-methylpiperazin-1-yl)but-1-ynyl]-3-quinolinecarbonitrile (SKS-927). Variation of the solubilizing amine tail or removal of the methoxy group from either C-6 of the quinoline core or C-5 of the aniline headpiece led to reduced activity.
Assuntos
Nitrilas/farmacologia , Quinolinas/farmacologia , Quinases da Família src/antagonistas & inibidores , Aminas , Compostos de Anilina , Humanos , Concentração Inibidora 50 , Nitrilas/síntese química , Quinolinas/síntese química , Solubilidade , Relação Estrutura-AtividadeRESUMO
New 4-phenylamino-3-quinolinecarbonitriles with a 7-ethynyl group substituted by a pyridine, phenyl or thiophene ring containing basic water solubilizing groups were prepared and evaluated as Src kinase inhibitors. Of these new analogs, potent activity was observed with compounds having a (2,4-dichloro-5-methoxyphenyl)amino group at C-4, a methoxy or ethoxy group at C-6, and a pyridyl group bearing a dimethylamine or N-methylpiperazine on the ethynyl group at C-7.
Assuntos
Quinolinas/farmacologia , Água/química , Quinases da Família src/antagonistas & inibidores , Quinolinas/química , SolubilidadeRESUMO
7-[(2,4-Dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitriles with various heteroaryl groups at C-2 are inhibitors of Src kinase activity. Of these new analogs, compounds substituted at C-2 by a 3,5-furan or a 2,5-pyridine had the best activity in the Src enzyme and cell assays.
Assuntos
Nitrilas/síntese química , Inibidores de Proteínas Quinases/síntese química , Quinases da Família src/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Cinética , Camundongos , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-AtividadeRESUMO
2-phenyl-7-phenylaminothieno[3,2-b]pyridine-6-carbonitriles were recently reported to be inhibitors of Src kinase activity. In this study we present structure-activity relationships for additional thieno[3,2-b]pyridine-6-carbonitriles, modifying the substituents on the C-2 phenyl and C-7 phenylamino groups. Derivatives with various aminomethyl and aminoethyl substituents on the para position of the C-2 phenyl group retained the activity of the initial analogues. However, direct attachment of an amino group led to decreased activity. A 2,4-dichloro-5-methoxyphenylamino group at C-7 provided superior inhibition of Src enzymatic activity. Replacement of the C-2 phenyl group with a 3,5-substituted thiophene led to improved Src inhibitory activity compared to the parent compound, but other thiophene isomers were less active. One of the analogues reported here exhibited in vivo activity comparable to that of SKI-606, a related 3-quinolinecarbonitrile currently in clinical trials.
Assuntos
Antineoplásicos/síntese química , Nitrilas/síntese química , Piridinas/síntese química , Tiofenos/síntese química , Quinases da Família src/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Humanos , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/genética , Camundongos , Camundongos Nus , Nitrilas/química , Nitrilas/farmacologia , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologia , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/genéticaRESUMO
Several new ethynyl- and ethenyl-4-phenylamino-3-quinolinecarbonitriles were synthesized and tested for Src inhibition. Derivatives bearing an ethenyl or ethynyl substituent at C-6 showed decreased Src inhibitory activity. Incorporation of an ethenylpyridine N-oxide group at C-7 provided 20b, a 0.6 nM inhibitor of Src enzymatic activity with excellent cellular potency.
Assuntos
Quinolinas/química , Quinases da Família src/antagonistas & inibidores , Animais , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Modelos Químicos , Estrutura Molecular , Quinolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
We disclose here a new class of kinase inhibitors, obtained by replacing the phenyl ring of a 3-quinolinecarbonitrile system with a thiophene ring. When suitably substituted, the resultant 7-phenylaminothieno[3,2-b]pyridine-6-carbonitrile analogues show potent inhibition of Src kinase activity.
Assuntos
Inibidores Enzimáticos/síntese química , Piridinas/síntese química , Tiofenos/síntese química , Quinases da Família src/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Piridinas/farmacologia , Relação Estrutura-Atividade , Tiofenos/farmacologiaRESUMO
A series of 7-ethynyl and 7-ethenyl-4-anilino-3-quinolinecarbonitriles were synthesized and tested for Src inhibition. Derivatives bearing a C-6 methoxy group and 2,4-dichloro-5-methoxyaniline at C-4 showed optimal inhibition of Src enzymatic and cellular activity. The ethenyl and ethynyl groups were incorporated at C-7 utilizing a Stille, Heck, or Sonogashira coupling reaction.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Nitrilas/síntese química , Nitrilas/farmacologia , Quinases da Família src/antagonistas & inibidores , Inibidores Enzimáticos/química , Nitrilas/químicaRESUMO
We previously reported that several 7-alkoxy-4-phenylamino-3-quinolinecarbonitriles were potent inhibitors of Src kinase activity. We disclose here a new highly efficient and versatile route to these compounds, which are also potent inhibitors of Abl kinase.
Assuntos
Nitrilas/síntese química , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinolinas/síntese química , Quinases da Família src/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Nitrilas/química , Nitrilas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Several 7-alkoxy-4-anilino-3-quinolinecarbonitriles were synthesized and evaluated for Src kinase inhibitory activity. Optimal inhibition of both Src enzymatic and cellular activity was seen with analogues having a 2,4-dichloro-5-methoxyaniline group at C-4. Compound 18, which has a 1-methylpiperidinemethoxy group at C-7, showed in vivo activity in a xenograft model.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Nitrilas/síntese química , Nitrilas/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Quinases da Família src/antagonistas & inibidores , Animais , Linhagem Celular , Transplante de Células , Fibroblastos/enzimologia , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Camundongos Nus , Ratos , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
A short synthesis of the hydantoin-containing marine sponge metabolites axinohydantoins is described. A key feature of the synthesis is a putative biomimetic, intramolecular cyclization of alpha-functionalized imidazolone 5, which affords the tricyclic pyrroloazepinone framework comprising 6. In addition, the conversion of imidazolones to alpha,beta-unsaturated hydantoins is outlined and represents a new approach to these heterocyclic systems.