RESUMEN
Angiogenesis is vital for solid tumor growth, and its prevention is a proven strategy for the treatment of disease states such as cancer. The vascular endothelial growth factor (VEGF) pathway provides several opportunities by which small molecules can act as inhibitors of endothelial proliferation and migration. Critical to these processes is signaling through VEGFR-2 or the kinase insert domain receptor (KDR) upon stimulation by its ligand VEGF. Herein, we report the discovery of 2,3-dihydro-1,4-benzoxazines as inhibitors of intrinsic KDR activity (IC 50 < 0.1 microM) and human umbilical vein endothelial cell (HUVEC) proliferation with IC 50 < 0.1 microM. More specifically, compound 16 was identified as a potent (KDR: < 1 nM and HUVEC: 4 nM) and selective inhibitor that exhibited efficacy in angiogenic in vivo models. In addition, this series of molecules is typically well-absorbed orally, further demonstrating the 2,3-dihydro-1,4-benzoxazine moiety as a promising platform for generating kinase-based antiangiogenic therapeutic agents.
Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Benzoxazinas/administración & dosificación , Neoplasias/irrigación sanguínea , Neovascularización Patológica/prevención & control , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Animales , Benzoxazinas/síntesis química , Benzoxazinas/química , Disponibilidad Biológica , Línea Celular , Proliferación Celular/efectos de los fármacos , Neovascularización de la Córnea/sangre , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Células Endoteliales/efectos de los fármacos , Femenino , Humanos , Inyecciones Subcutáneas , Ligandos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Animales , Modelos Moleculares , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
We have previously shown N-arylnaphthamides can be potent inhibitors of vascular endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted naphthamides were prepared and found to yield nanomolar inhibitors of VEGFR-2 (KDR) with an improved selectivity profile against a panel of tyrosine and serine/threonine kinases. The inhibitory activity of this series was retained at the cellular level. Naphthamides 3, 20, and 22 exhibited good pharmacokinetics following oral dosing and showed potent inhibition of VEGF-induced angiogenesis in the rat corneal model. Once-daily oral administration of 22 for 14 days led to 85% inhibition of established HT29 colon cancer and Calu-6 lung cancer xenografts at doses of 10 and 20 mg/kg, respectively.
Asunto(s)
Antineoplásicos/farmacología , Células Endoteliales/efectos de los fármacos , Naftalenos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neovascularización de la Córnea/sangre , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Concentración 50 Inhibidora , Inyecciones Intravenosas , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Microsomas Hepáticos/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Naftalenos/síntesis química , Naftalenos/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of naphthyl-based compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptors. Investigations of structure-activity relationships led to the identification of a series of naphthamides that are potent inhibitors of the VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, and of these several compounds possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48 demonstrated significant antitumor efficacy against established HT29 human colon adenocarcinoma xenografts implanted in athymic mice. A full account of the preparation, structure-activity relationships, pharmacokinetic properties, and pharmacology of analogues within this series is presented.