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1.
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
3.
Bioorg Med Chem Lett ; 22(9): 3050-5, 2012 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-22497760

RESUMEN

A new series of quinoline ether inhibitors, which potently and selectively inhibit PDGFR tyrosine kinases, is described in this Letter. Compounds 23 and 33 are selective, low nanomolar inhibitors of PDGFRα and ß, display good pharmacokinetics in rat and dog and are active in vivo at low doses when given orally twice daily. Further evaluation of these compounds is warranted.


Asunto(s)
Éteres/farmacología , Quinolinas/farmacología , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Animales , Perros , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Ratas
4.
Bioorg Med Chem Lett ; 18(6): 1904-9, 2008 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-18294849

RESUMEN

A new class of 1-acetanilide-4-aminopyrazole-substituted quinazoline Aurora kinase inhibitors has been discovered possessing highly potent cellular activity. Continuous infusion into athymic mice bearing SW620 tumors of the soluble phosphate derivative 2 led to dose-proportional exposure of the des-phosphate compound 8 with a high-unbound fraction. The combination of potent cell activity and high free-drug exposure led to pharmacodynamic changes in the tumor at low doses, indicative of Aurora B-kinase inhibition and a reduction in tumor volume.


Asunto(s)
Neoplasias del Colon/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/química , Quinazolinas/síntesis química , Quinazolinas/farmacología , Animales , Aurora Quinasa B , Aurora Quinasas , Ciclo Celular/efectos de los fármacos , Neoplasias del Colon/enzimología , Neoplasias del Colon/patología , Citocromo P-450 CYP3A/metabolismo , Electrofisiología , Canales de Potasio Éter-A-Go-Go/metabolismo , Histonas/metabolismo , Humanos , Masculino , Ratones , Ratones Desnudos , Estructura Molecular , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Quinazolinas/química , Ratas , Ratas Wistar , Relación Estructura-Actividad , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
5.
J Med Chem ; 50(9): 2213-24, 2007 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-17373783

RESUMEN

The Aurora kinases have been the subject of considerable interest as targets for the development of new anticancer agents. While evidence suggests inhibition of Aurora B kinase gives rise to the more pronounced antiproliferative phenotype, the most clinically advanced agents reported to date typically inhibit both Aurora A and B. We have discovered a series of pyrazoloquinazolines, some of which show greater than 1000-fold selectivity for Aurora B over Aurora A kinase activity, in recombinant enzyme assays. These compounds have been designed for parenteral administration and achieve high levels of solubility by virtue of their ability to be delivered as readily activated phosphate derivatives. The prodrugs are comprehensively converted to the des-phosphate form in vivo, and the active species have advantageous pharmacokinetic properties and safety pharmacology profiles. The compounds display striking in vivo activity, and compound 5 (AZD1152) has been selected for clinical evaluation and is currently in phase 1 clinical trials.


Asunto(s)
Antineoplásicos/síntesis química , Organofosfatos/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/síntesis química , Quinazolinas/síntesis química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Aurora Quinasa A , Aurora Quinasa B , Aurora Quinasas , División Celular/efectos de los fármacos , Línea Celular Tumoral , Inhibidores Enzimáticos del Citocromo P-450 , Ensayos de Selección de Medicamentos Antitumorales , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Femenino , Histonas/metabolismo , Humanos , Masculino , Ratones , Ratones Desnudos , Organofosfatos/farmacocinética , Organofosfatos/farmacología , Fosforilación , Profármacos/síntesis química , Profármacos/farmacocinética , Profármacos/farmacología , Unión Proteica , Pirazoles/farmacocinética , Pirazoles/farmacología , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Relación Estructura-Actividad , Trasplante Heterólogo
6.
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
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