RESUMEN
Extensive efforts are under way to identify antiangiogenic therapies for the treatment of human cancers. Many proposed therapeutics target vascular endothelial growth factor (VEGF) or the kinase insert domain receptor (KDR/VEGF receptor-2/FLK-1), the mitogenic VEGF receptor tyrosine kinase expressed by endothelial cells. Inhibition of KDR catalytic activity blocks tumor neoangiogenesis, reduces vascular permeability, and, in animal models, inhibits tumor growth and metastasis. Using a gene expression profiling strategy in rat tumor models, we identified a set of six genes that are selectively overexpressed in tumor endothelial cells relative to tumor cells and whose pattern of expression correlates with the rate of tumor endothelial cell proliferation. In addition to being potential targets for antiangiogenesis tumor therapy, the expression patterns of these genes or their protein products may aid the development of pharmacodynamic assays for small molecule inhibitors of the KDR kinase in human tumors.
Asunto(s)
Biomarcadores de Tumor , Perfilación de la Expresión Génica/métodos , Inhibidores de la Angiogénesis/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular , Cartilla de ADN/química , Células Endoteliales/citología , Endotelio Vascular/citología , Humanos , Inmunohistoquímica , Microcirculación/citología , Microscopía Fluorescente , Metástasis de la Neoplasia , Trasplante de Neoplasias , Neovascularización Patológica , Análisis de Secuencia por Matrices de Oligonucleótidos , Ratas , Ratas Endogámicas F344 , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
A series of N-(1,3-thiazol-2-yl)pyridin-2-amine KDR kinase inhibitors have been developed that possess optimal properties. Compounds have been discovered that exhibit excellent in vivo potency. The particular challenges of overcoming hERG binding activity and QTc increases in vivo in addition to achieving good pharmacokinetics have been acomplished by discovering a unique class of amine substituents. These compounds have a favorable kinase selectivity profile that can be accentuated with appropriate substitution.
Asunto(s)
Aminopiridinas/síntesis química , Canales de Potasio con Entrada de Voltaje/metabolismo , Piridinas/síntesis química , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Tiazoles/síntesis química , Administración Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacología , Animales , Disponibilidad Biológica , Línea Celular , Perros , Canal de Potasio ERG1 , Electrocardiografía/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go , Técnicas In Vitro , Pulmón/enzimología , Macaca mulatta , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Fosforilación , Piridinas/farmacocinética , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Tiazoles/farmacocinética , Tiazoles/farmacología , Distribución Tisular , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
An azo-dye lead was modified to a novel N-(1,3-thiazol-2-yl)pyridin-2-amine series of KDR kinase inhibitors through the use of rapid analog libraries. This new class has been found to be potent, selective, and of low molecular weight. Molecular modeling has postulated an interesting conformational preference and binding mode for these compounds in the active site of the enzyme.
Asunto(s)
Aminas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Aminas/síntesis química , Sitios de Unión , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Unión Proteica , Conformación Proteica/efectos de los fármacos , Relación Estructura-Actividad , Termodinámica , Receptor 2 de Factores de Crecimiento Endotelial Vascular/químicaRESUMEN
Small molecule inhibitors of KDR kinase activity have typically possessed poor intrinsic physical properties including low aqueous solubility and high lipophilicity. These features have often conferred limited cell permeability manifested in low levels of cell-based KDR inhibitory activity and oral bioavailability. Thus, the design of inhibitors with appropriate physical properties has played a critical role in the development of clinical candidates. We present a variety of structural modifications that have afforded improvements in physical properties and thereby have addressed suboptimal cellular potency and pharmacokinetics for three unique classes of KDR kinase inhibitors.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Sitios de Unión , Disponibilidad Biológica , Permeabilidad de la Membrana Celular , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Modelos Moleculares , Estructura Molecular , Solubilidad , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/químicaRESUMEN
Modifications to the basic side-chain of early lead structures of the indolyl quinolinone class of KDR kinase inhibitors resulted in improved pharmacokinetic and ancillary profiles. Specifically, compounds bearing 5-amido- and 5-sulphonamido-indolyl substituents exhibited lower plasma clearance and weaker binding affinity for the I(Kr) potassium channel hERG.
Asunto(s)
Proteínas de Transporte de Catión/metabolismo , Inhibidores Enzimáticos/farmacocinética , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/metabolismo , Quinolonas/farmacocinética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Línea Celular , Perros , Inhibidores Enzimáticos/química , Canales de Potasio Éter-A-Go-Go , Humanos , Microsomas Hepáticos/enzimología , Unión Proteica/fisiología , Quinolonas/química , Ratas , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
We have discovered 3-(5-thien-3-ylpyridin-3-yl)-1H-indoles as potent inhibitors of KDR kinase activity. This communication details the evolution of this novel class from a potent screening lead of vastly different structure with an emphasis on structural modifications that retained activity and provided improvements in key physical properties. The synthesis and in-depth evaluation of these inhibitors are described.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Indoles/síntesis química , Indoles/farmacocinética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , Disponibilidad Biológica , Línea Celular , Semivida , Indoles/farmacología , Concentración 50 Inhibidora , Ratas , Relación Estructura-ActividadRESUMEN
1,5-Diarylbenzimidazoles have been identified as potent inhibitors of KDR kinase activity. The series was developed with a goal of finding compounds with optimal drug-like properties. This communication describes structural modifications in the series that enhance solubility, lower protein binding, and provide compounds with excellent potency and pharmacokinetic profiles.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Fenómenos Químicos , Química Física , Perros , Diseño de Fármacos , Inhibidores Enzimáticos/farmacocinética , Semivida , Concentración de Iones de Hidrógeno , Indicadores y Reactivos , Conformación Molecular , Ratas , Relación Estructura-ActividadRESUMEN
2,4-Disubstituted pyrimidines were synthesized as a novel class of KDR kinase inhibitors. Evaluation of the SAR of the screening lead compound 1 (KDR IC(50)=105 nM, Cell IC(50)=8% inhibition at 500 nM) led to the potent 3,5-dimethylaniline derivative 2d (KDR IC(50)=6 nM, cell IC(50)=19 nM).
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Pirimidinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Células Cultivadas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Pirimidinas/síntesis química , Relación Estructura-ActividadRESUMEN
We have introduced solubilizing functionality to a 3,6-disubstituted pyrazolo[1,5-a]pyrimidine series of KDR kinase inhibitors to improve the physical properties of these compounds. The addition of a basic side-chain to the 6-aryl ring, introduction of 3-pyridyl groups, and most significantly, incorporation of a 4-pyridinonyl substituent at the 6-position of the core are modifications that maintain and often enhance the intrinsic potency of this class of inhibitors. Moreover, the improvements in physical properties result in marked increases in cellular activity and more favorable pharmacokinetics in rats. The synthesis and SAR of these compounds are described.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Pirimidinas/farmacocinética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , División Celular/efectos de los fármacos , Línea Celular , Endotelio Vascular/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Tasa de Depuración Metabólica , Farmacocinética , Pirimidinas/síntesis química , Pirimidinas/farmacología , Ratas , Solubilidad , Relación Estructura-ActividadRESUMEN
We have synthesized and evaluated the activity of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines as a new class of KDR kinase inhibitors. Starting with screening lead 1, potency against isolated KDR was fully optimized with 3-thienyl and 4-methoxyphenyl substituents at the 6- and 3-positions (3g, KDR IC(50)=19 nM), respectively. The synthesis and SAR of these compounds are described.