RESUMEN
A novel series of N-(3-(6-substituted-aminopyridin-3-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting TrkA receptor tyrosine kinase was identified. SAR study of the series allowed us to design and synthesize compounds possessing inhibitory activity of TrkA kinase enzyme in the low nanomolar range with low residual activity against c-Met and with no significant activity against VEGFR2.
RESUMEN
A novel series of N-(3-fluoro-4-(2-substituted-thieno[3,2-b]pyridin-7-yloxy)phenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamides targeting RON receptor tyrosine kinase was designed and synthesized. SAR study of the series allowed us to identify compounds possessing either inhibitory activity of RON kinase enzyme in the low nanomolar range with low residual activity against the closely related c-Met or potent dual inhibitory activity against RON and c-Met, with no significant activity against VEGFR2 in both cases.
Asunto(s)
Antineoplásicos/química , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Humanos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacocinética , Ratas , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of malonamide-type dual VEGFR2/c-Met inhibitors in which one of the amide bonds was replaced by an amide isostere-a trifluoroethylamine unit, was designed, synthesized, and evaluated for their enzymatic and cellular inhibition of VEGFR2 and c-Met enzymes. Optimization of these molecular entities resulted in identification of potent and selective inhibitors of VEGFR2 enzyme.
Asunto(s)
Amidas/química , Inhibidores de Proteínas Quinasas/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Amidas/farmacología , Técnicas de Cocultivo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/enzimología , Fibroblastos/efectos de los fármacos , Fibroblastos/enzimología , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
A family of thieno[3,2-b]pyridine based small molecule inhibitors of c-Met and VEGFR2 were designed based on lead structure 2. These compounds were shown to have IC(50) values in the low nanomolar range in vitro and were efficacious in human tumor xenograft models in mice in vivo.
Asunto(s)
Antineoplásicos/química , Malonatos/química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Piridinas/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Humanos , Malonatos/síntesis química , Malonatos/farmacocinética , Ratones , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinéticaRESUMEN
A series of N-(4-(6,7-disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.
Asunto(s)
Amidas/química , Imidazolidinas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-met/administración & dosificación , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Amidas/farmacología , Animales , Línea Celular Tumoral , Células HCT116 , Humanos , Imidazolidinas/farmacología , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.
Asunto(s)
Benzamidas/farmacología , Inhibidores Enzimáticos/farmacología , Pirimidinas/farmacología , Animales , Antineoplásicos/farmacología , Benzamidas/síntesis química , Línea Celular Tumoral , Proliferación Celular , Química Farmacéutica/métodos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores de Histona Desacetilasas , Humanos , Concentración 50 Inhibidora , Ratones , Trasplante de Neoplasias , Pirimidinas/síntesis química , Relación Estructura-ActividadRESUMEN
The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.
Asunto(s)
Benzamidas/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Pirimidinas/farmacología , Administración Oral , Animales , Benzamidas/administración & dosificación , Benzamidas/química , Perros , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Masculino , Pirimidinas/administración & dosificación , Pirimidinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs is described. Some of these compounds were shown to inhibit HDAC1 with IC(50) values below the micromolar range, induce hyperacetylation of histones, upregulate expression of the tumor suppressor p21(WAF1/Cip1), and inhibit proliferation of human cancer cells. In addition, certain compounds of this class were active in several human tumor xenograft models in vivo.
Asunto(s)
Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Compuestos de Anilina/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Benzamidas/química , Mama/citología , Mama/efectos de los fármacos , Línea Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Inhibidores Enzimáticos/química , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células HCT116 , Histona Desacetilasa 1 , Humanos , Imidazoles/síntesis química , Imidazoles/química , Imidazoles/farmacología , Relación Estructura-ActividadRESUMEN
Inhibition of histone deacetylases (HDAC) is emerging as a new strategy in human cancer therapy. The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides is presented herein. From the different series bearing a six-membered heteroaromatic ring studied, the s-triazine series showed the best HDAC1 enzyme and in vitro anti-proliferative activities with IC(50) values below micromolar range. Some of these compounds can also significantly reduce tumor growth in human tumor xenograft models in mice.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Pirimidinas/farmacología , Triazinas/síntesis química , Triazinas/farmacología , Animales , Antineoplásicos/química , Benzamidas/química , Modelos Animales de Enfermedad , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Ratones , Relación Estructura-Actividad , Triazinas/químicaRESUMEN
A variety of N-(2-amino-phenyl)-4-(heteroarylmethyl)-benzamides were designed and synthesized. These compounds were shown to inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induced hyperacetylation of histones, induced the expression of the tumor suppressor protein p21(WAF1/Cip1), and inhibited cellular proliferation. Certain compounds of this class also showed in vivo activity in various human tumor xenograft models in mice.
Asunto(s)
Benzamidas/química , Benzamidas/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Aminación , Animales , Sitios de Unión , Línea Celular , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Metilación , Ratones , Modelos Moleculares , Estructura Molecular , Niacina/farmacología , Relación Estructura-Actividad , Urea/química , Vasodilatación/efectos de los fármacos , ortoaminobenzoatos/químicaRESUMEN
Inhibition of histone deacetylases (HDACs) is emerging as a new strategy in human cancer therapy. Novel 2-aminophenyl benzamides and acrylamides, that can inhibit human HDAC enzymes and induce hyperacetylation of histones in human cancer cells, have been designed and synthesized. These compounds selectively inhibit proliferation and cause cell cycle arrest in various human cancer cells but not in normal cells. The growth inhibition of 2-aminophenyl benzamides and acrylamides against human cancer cells in vitro is reversible and is dependent on the induction of histone acetylation. Compounds of this class can significantly reduce tumor growth in human tumor xenograft models.