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
A novel estrogen receptor down-regulator, 7-hydroxycoumarin (5, SS5020), has been reported with antitumor effects against chemically induced mammary tumors. Here, we report on our own investigation of 7-hydroxycoumarins as potential selective estrogen receptor down-regulators, which led us to the discovery of potent down-regulating antagonists, such as 33. Subsequent optimization and removal of the 7-hydroxy group led to coumarin 59, which had increased potency and improved rat bioavailability relative to SS5020.
Asunto(s)
Receptor alfa de Estrógeno/metabolismo , Umbeliferonas/química , Umbeliferonas/farmacología , Administración Oral , Animales , Línea Celular Tumoral , Cumarinas/química , Cumarinas/farmacocinética , Cumarinas/farmacología , Regulación hacia Abajo/efectos de los fármacos , Receptor alfa de Estrógeno/análisis , Humanos , Simulación del Acoplamiento Molecular , Ratas , Umbeliferonas/farmacocinéticaRESUMEN
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.
Asunto(s)
Compuestos de Anilina/síntesis química , Cromonas/síntesis química , Neoplasias Experimentales/tratamiento farmacológico , Fosfohidrolasa PTEN/deficiencia , Inhibidores de las Quinasa Fosfoinosítidos-3 , Compuestos de Anilina/farmacología , Animales , Cromonas/farmacología , Perros , Descubrimiento de Drogas , Humanos , Masculino , Ratones , Neoplasias Experimentales/química , Relación Estructura-ActividadRESUMEN
Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain.
Asunto(s)
Amidas/farmacología , Benzotiazoles/farmacología , Dolor/tratamiento farmacológico , Canales Catiónicos TRPV/antagonistas & inhibidores , Amidas/administración & dosificación , Amidas/química , Animales , Benzotiazoles/administración & dosificación , Benzotiazoles/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Inflamación/tratamiento farmacológico , Estructura Molecular , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Solubilidad , Relación Estructura-ActividadRESUMEN
4-(1,3-Benzothiazol-2-yl)thiophene-2-sulfonamide (4a) was found to be a moderately potent inhibitor of cyclin-dependent kinase 5 (cdk5) from a HTS screen. The synthesis and SAR around this hit is described. The X-ray coordinates of ligand 4a with cdk5 are also reported, showing an unusual binding mode to the hinge region via a water molecule.