RESUMEN
A series of amino acid ester prodrugs of the dual VEGFR-2/FGFR-1 kinase inhibitor 1 (BMS-540215) was prepared in an effort to improve the aqueous solubility and oral bioavailability of the parent compound. These prodrugs were evaluated for their ability to liberate parent drug 1 in in vitro and in vivo systems. The l-alanine prodrug 8 (also known as brivanib alaninate/BMS-582664) was selected as a development candidate and is presently in phase II clinical trials.
Asunto(s)
Carcinoma/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Profármacos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/farmacología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Triazinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Alanina/análogos & derivados , Animales , Disponibilidad Biológica , Proliferación Celular/efectos de los fármacos , Ensayos Clínicos Fase II como Asunto , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Intestinos/efectos de los fármacos , Hígado/efectos de los fármacos , Ratones , Microsomas/efectos de los fármacos , Estructura Molecular , Profármacos/síntesis química , Profármacos/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirroles/síntesis química , Pirroles/química , Solubilidad , Estereoisomerismo , Triazinas/síntesis química , Triazinas/química , Agua/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Substituted 3-((2-(pyridin-2-ylamino)thiazol-5-ylmethyl)amino)benzamides were identified as potent and selective inhibitors of vascular endothelial growth factor receptor-2 (VEGFR-2) kinase activity. The enzyme kinetics associated with the VEGFR-2 inhibition of 14 (Ki=49+/-9 nM) confirmed that the aminothiazole-based analogues are competitive with ATP. Analogue 14 demonstrated excellent kinase selectivity, favorable pharmacokinetic properties in multiple species, and robust in vivo efficacy in human lung and colon carcinoma xenograft models.
Asunto(s)
Aminopiridinas/síntesis química , Inhibidores de la Angiogénesis/síntesis química , Tiazoles/síntesis química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacología , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , Sitios de Unión , Proliferación Celular , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Endotelio Vascular/citología , Humanos , Técnicas In Vitro , Macaca fascicularis , Ratones , Ratones Desnudos , Modelos Moleculares , Ratas , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacología , Venas Umbilicales/citología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of substituted 4-(2,4-difluoro-5-(methoxycarbamoyl)phenylamino)pyrrolo[2,1-f][1,2,4]triazines was identified as potent and selective inhibitors of the tyrosine kinase activity of the growth factor receptors VEGFR-2 (Flk-1, KDR) and FGFR-1. The enzyme kinetics associated with the VEGFR-2 inhibition of compound 50 (K(i) = 52 +/- 3 nM) confirmed that the pyrrolo[2,1-f][1,2,4]triazine analogues are competitive with ATP. Several analogues demonstrated low-nanomolar inhibition of VEGF- and FGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation. Replacement of the C6-ester substituent of the pyrrolo[2,1-f][1,2,4]triazine core with heterocyclic bioisosteres, such as substituted 1,3,5-oxadiazoles, afforded compounds with excellent oral bioavailability in mice (i.e., 50 F(po) = 79%). Significant antitumor efficacy was observed with compounds 44, 49, and 50 against established L2987 human lung carcinoma xenografts implanted in athymic mice. A full account of the synthesis, structure-activity relationships, pharmacology, and pharmacokinetic properties of analogues within the series is presented.