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1.
Bioorg Med Chem Lett ; 27(13): 3030-3035, 2017 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-28526367

RESUMEN

We report the discovery of a novel aminopyrazine series of PI3Kα inhibitors, designed by hybridizing two known scaffolds of PI3K inhibitors. We describe the progress achieved from the first compounds plagued with poor general kinase selectivity to compounds showing high selectivity for PI3Kα over PI3Kß and excellent general kinase selectivity. This effort culminated with the identification of compound 5 displaying high potency and selectivity, and suitable physiochemical and pharmacokinetic properties for oral administration. In vivo, compound 5 showed good inhibition of tumour growth (86% tumour growth inhibition at 50mg/kg twice daily orally) in the MCF7 xenograft model in mice.


Asunto(s)
Descubrimiento de Drogas , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/farmacología , Fosfatidilinositol 3-Quinasa Clase I , Relación Dosis-Respuesta a Droga , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazinas/síntesis química , Pirazinas/química , Relación Estructura-Actividad
2.
Bioorg Med Chem Lett ; 25(22): 5155-62, 2015 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-26475521

RESUMEN

Starting from potent inhibitors of PI3Kα having poor general kinase selectivity (e.g., 1 and 2), optimisation of this series led to the identification of 25, a potent inhibitor of PI3Kα (wild type, E545K and H1047R mutations) and PI3Kδ, selective versus PI3Kß and PI3Kγ, with excellent general kinase selectivity. Compound 25 displayed low metabolic turnover and suitable physical properties for oral administration. In vivo, compound 25 showed pharmacodynamic modulation of AKT phosphorylation and near complete inhibition of tumour growth (93% tumour growth inhibition) in a murine H1047R PI3Kα mutated SKOV-3 xenograft tumour model after chronic oral administration at 25mg/kg b.i.d. Compound 25, also known as AZD8835, is currently in phase I clinical trials.


Asunto(s)
Antineoplásicos/farmacología , Oxadiazoles/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Perros , Humanos , Ratones , Ratones Desnudos , Ratones SCID , Simulación del Acoplamiento Molecular , Oxadiazoles/síntesis química , Piperidinas/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Bioorg Med Chem Lett ; 18(6): 1799-803, 2008 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-18313293

RESUMEN

We have identified a new series of C-5 substituted indazolylaminoquinazolines as potent erbB2 kinase inhibitors. The lead compound 22 showed excellent in vitro potency, good physical properties, acceptable oral pharmacokinetics in rat and dog, and low human in vitro clearance. It showed at least equivalent activity dose for dose compared to lapatinib in various erbB2- or EGFR-driven xenograft models after chronic oral administration.


Asunto(s)
Antineoplásicos/farmacología , Receptores ErbB/antagonistas & inhibidores , Indazoles/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Perros , Factor de Crecimiento Epidérmico/farmacología , Canales de Potasio Éter-A-Go-Go , Femenino , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Indazoles/síntesis química , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Lapatinib , Masculino , Tasa de Depuración Metabólica , Ratones , Ratones Desnudos , Ratones SCID , Microsomas/efectos de los fármacos , Estructura Molecular , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Quinazolinas/síntesis química , Ratas , Ratas Wistar , Tasa de Supervivencia , Ensayos Antitumor por Modelo de Xenoinjerto
7.
J Med Chem ; 49(3): 955-70, 2006 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-16451062

RESUMEN

The synthesis of a novel series of quinazolines substituted at C4 by five-membered ring aminoheterocycles is reported. Their in vitro structure-activity relationships versus Aurora A and B serine-threonine kinases is discussed. Our results demonstrate that quinazolines with a substituted aminothiazole at C4 possess potent Aurora A and B inhibitory activity and excellent selectivity against a panel of various serine-threonine and tyrosine kinases, as exemplified by compound 46. We found also that the position and nature of the substituent on the thiazole play key roles in cellular potency. Compounds with an acetanilide substituent at C5' have the greatest cellular activity. The importance of the C5' position for substitution has been rationalized by ab initio molecular orbital calculations. Results show that the planar conformation with the sulfur of the thiazole next to the quinazoline N-3 is strongly favored over the other possible planar conformation. Compound 46 is a potent suppressor of the expression of phospho-histone H3 in tumor cells in vitro as well as in vivo, where 46, administered as its phosphate prodrug 54, suppresses the expression of phospho-histone H3 in subcutaneously implanted tumors in nude mice.


Asunto(s)
Antineoplásicos/síntesis química , Organofosfatos/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Quinazolinas/síntesis química , Tiazoles/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Aurora Quinasa A , Aurora Quinasas , Línea Celular Tumoral , Histonas/antagonistas & inhibidores , Histonas/biosíntesis , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Trasplante de Neoplasias , Organofosfatos/química , Organofosfatos/farmacología , Fosfoproteínas/antagonistas & inhibidores , Fosfoproteínas/biosíntesis , Profármacos/síntesis química , Profármacos/química , Profármacos/farmacología , Proteínas Serina-Treonina Quinasas/química , Teoría Cuántica , Quinazolinas/química , Quinazolinas/farmacología , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Bioorg Med Chem Lett ; 15(24): 5446-9, 2005 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-16203139

RESUMEN

A series of 5,7-disubstituted quinazolines, bearing 4-heteroaryl substituents such as 2-pyridinylamine or 2-pyrazinylamine, has been synthetised and evaluated as c-Src kinase inhibitors. Highly potent inhibition, high selectivity and physical properties suitable for oral dosing were achieved within this series: 23d and 42 were identified as sub-0.1muM inhibitors in a c-Src-driven cell proliferation assay and displayed adequate rat pharmacokinetics after oral administration.


Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacología , Animales , Proteína Tirosina Quinasa CSK , División Celular , Inhibidores Enzimáticos/farmacocinética , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacocinética , Compuestos Heterocíclicos/farmacología , Isomerismo , Cinética , Modelos Moleculares , Quinazolinas/síntesis química , Quinazolinas/farmacología , Ratas , Familia-src Quinasas
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