RESUMEN
Attempts to lock the active conformation of compound 4, a PI3Kß/δ inhibitor (PI3Kß cell IC50 0.015µM), led to the discovery of a series of 8-(1-phenylpyrrolidin-2-yl)-6-carboxamide-2-morpholino-4H-chromen-4-ones, which showed high levels of potency and selectivity as PI3Kß/δ inhibitors. Compound 10 proved exquisitely potent and selective: PI3Kß cell IC50 0.0011µM in PTEN null MDA-MB-468 cell and PI3Kδ cell IC50 0.014µM in Jeko-1 B-cell, and exhibited suitable physical properties for oral administration. In vivo, compound 10 showed profound pharmacodynamic modulation of AKT phosphorylation in a mouse PTEN-null PC3 prostate tumour xenograft after a single oral dose and gave excellent tumour growth inhibition in the same model after chronic oral dosing. Based on these results, compound 10 was selected as one of our PI3Kß/δ preclinical candidates.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/uso terapéutico , Benzopiranos/química , Benzopiranos/uso terapéutico , Fosfohidrolasa PTEN/genética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Benzopiranos/farmacocinética , Benzopiranos/farmacología , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Perros , Eliminación de Gen , Humanos , Masculino , Ratones Desnudos , Simulación del Acoplamiento Molecular , Morfolinos/química , Morfolinos/farmacocinética , Morfolinos/farmacología , Morfolinos/uso terapéutico , Próstata/efectos de los fármacos , Próstata/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
We report the discovery and optimisation of a series of 8-(2,3-dihydro-1,4-benzoxazin-4-ylmethyl)-2-morpholino-4-oxo-chromene-6-carboxamides, leading to compound 16 as a potent and selective PI3Kß/δ inhibitor: PI3Kß cell IC50 0.012 µM (in PTEN null MDA-MB-468 cell) and PI3Kδ cell IC50 0.047 µM (in Jeko-1 B-cell), with good pharmacokinetics and physical properties. In vivo, 16 showed profound pharmacodynamic modulation of AKT phosphorylation in a mouse PTEN-deficient PC3 prostate tumour xenograft after a single oral dose and gave excellent tumour growth inhibition in the same model after chronic oral dosing. Compound 16 was selected as a preclinical candidate for the treatment of PTEN-deficient tumours.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Isoenzimas/antagonistas & inhibidores , Morfolinos/química , Morfolinos/farmacología , Fosfohidrolasa PTEN/genética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Animales , Línea Celular Tumoral , Humanos , Ratones , FosforilaciónRESUMEN
Potent antagonists of the integrin α(5)ß(1), which are RGD mimetics built from tyrosine are described. This letter describes the optimization of in vitro potency obtained by variation of two parts of the molecule, the basic group and the linker between the basic group and the phenyl central core.
Asunto(s)
Integrina alfa5beta1/antagonistas & inhibidores , Oligopéptidos/síntesis química , Tirosina/análogos & derivados , Tirosina/síntesis química , Adhesión Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fibrinógeno/química , Fibronectinas/química , Humanos , Integrina alfa5beta1/metabolismo , Células K562 , Modelos Moleculares , Imitación Molecular , Oligopéptidos/farmacología , Albúmina Sérica/química , Relación Estructura-Actividad , Tirosina/farmacologíaRESUMEN
Potent antagonists of the integrin α(5)ß(1), which are RGD mimetics built from tyrosine are described. This paper describes the optimization of in vitro potency obtained by variation of two parts of the molecule, the central aromatic core and the amide moiety.
Asunto(s)
Integrina alfa5beta1/antagonistas & inhibidores , Oligopéptidos/síntesis química , Tirosina/análogos & derivados , Tirosina/síntesis química , Adhesión Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fibrinógeno/química , Fibronectinas/química , Humanos , Integrina alfa5beta1/metabolismo , Células K562 , Modelos Moleculares , Imitación Molecular , Oligopéptidos/farmacología , Albúmina Sérica/química , Relación Estructura-Actividad , Tirosina/farmacologíaRESUMEN
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 HeterólogoRESUMEN
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 XenoinjertoRESUMEN
Several studies have highlighted the dependency of PTEN deficient tumors to PI3Kß activity and specific inhibition of PI3Kδ has been shown activity against human B-cell cancers. We describe the discovery and optimization of a series of 8-(1-anilino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamides as PI3Kß/δ inhibitors, which led to the discovery of the clinical candidate 13, also known as AZD8186. On the basis of the lower lipophilicity of the chromen-4-one core compared to the previously utilized pyrido[1,2-a]pyrimid-4-one core, this series of compounds displayed high metabolic stability and suitable physical properties for oral administration. Compound 13 showed profound pharmacodynamic modulation of p-Akt in PTEN-deficient PC3 prostate tumor bearing mice after oral administration and showed complete inhibition of tumor growth in the mouse PTEN-deficient PC3 prostate tumor xenograft model. 13 was selected as a clinical candidate for treatment of PTEN-deficient cancers and has recently entered phase I clinical trials.