RESUMEN
Following the discovery of imidazopyridine 1 as a potent IGF-1R tyrosine kinase inhibitor, the aniline part has been modified with the aim to optimize the properties of this series. The structure-activity relationships against IGF-1R kinase activity as well as inhibition of the hERG ion channel are discussed.
Asunto(s)
Compuestos de Anilina/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Descubrimiento de Drogas , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Piridinas/síntesis química , Piridinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
We disclose a novel series of insulin-like growth factor-1 receptor kinase inhibitors based on the 3-(pyrimidin-4-yl)-imidazo[1,2-a]pyridine scaffold. The influence on the inhibitory activity of substitution on the imidazopyridine and at the C5 position of the pyrimidine is discussed. In the course of this optimization, we discovered a potent and selective inhibitor with suitable pharmacokinetics for oral administration.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Perros , Humanos , Ratones , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Piridinas/síntesis química , Piridinas/química , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Distribución TisularRESUMEN
Optimization of our bis-anilino-pyrimidine series of EphB4 kinase inhibitors led to the discovery of compound 12 which incorporates a key m-hydroxymethylene group on the C4 aniline. 12 displays a good kinase selectivity profile, good physical properties and pharmacokinetic parameters, suggesting it is a suitable candidate to investigate the therapeutic potential of EphB4 kinase inhibitors.
Asunto(s)
Compuestos de Anilina/química , Alcohol Bencilo/química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Receptor EphB4/antagonistas & inhibidores , Administración Oral , Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacocinética , Animales , Alcohol Bencilo/síntesis química , Alcohol Bencilo/farmacocinética , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Ratones , Ratones Desnudos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Receptor EphB4/metabolismo , Relación Estructura-ActividadRESUMEN
Starting from the initial bis-anilinopyrimidine 1, good potency against EphB4 was retained when benzodioxole at C-4 was replaced by an indazole. The key interactions of the indazole with the protein were characterised by crystallographic studies. Further optimisation led to compound 20, a potent inhibitor of the EphB4 and Src kinases with good pharmacokinetics in various preclinical species and high fraction unbound in plasma. Compound 20 may be used as a tool for evaluating the potential of EphB4 kinase inhibitors in vivo.
Asunto(s)
Benzodioxoles/síntesis química , Benzodioxoles/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptor EphB4/antagonistas & inhibidores , Animales , Benzodioxoles/farmacocinética , Células CHO , Cricetinae , Cricetulus , Cristalografía por Rayos X , Perros , Femenino , Masculino , Ratones , Ratones Desnudos , Modelos Moleculares , Fosforilación , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Ratas Wistar , Relación Estructura-Actividad , Especificidad por Sustrato , Familia-src Quinasas/antagonistas & inhibidoresRESUMEN
Novel 4-anilino-1H-pyrazolo[3,4-d]pyrimidines have been synthesized and evaluated in vitro for erbB2 and EGFR kinase inhibition. A representative compound displaying oral bioavailability in rat and dog illustrates the potential of this series to provide orally active erbB2 inhibitors.
Asunto(s)
Inhibidores de Proteínas Quinasas/antagonistas & inhibidores , Pirazoles/síntesis química , Pirazoles/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Receptor ErbB-2/antagonistas & inhibidores , Animales , Técnicas Químicas Combinatorias , Perros , Diseño de Fármacos , Estructura Molecular , Pirazoles/administración & dosificación , Pirazoles/química , Pirimidinas/administración & dosificación , Pirimidinas/química , RatasRESUMEN
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 XenoinjertoRESUMEN
Starting from initial lead 1 containing a basic 5-substituent, optimisation of the glycolamide-derived neutral 5-substituent led to potent inhibitors of erbB2 with good pharmacokinetics. Representative compounds 19 and 21 inhibited phosphorylation of erbB2 in a mouse BT474C xenograft model after oral administration.
Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Administración Oral , Animales , Línea Celular , Espectroscopía de Resonancia Magnética , Ratones , Trasplante de Neoplasias , Fosforilación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Quinazolinas/administración & dosificación , Quinazolinas/química , Quinazolinas/farmacocinética , Relación Estructura-ActividadRESUMEN
ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (<50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). These efforts resulted in the discovery of 64 (AZD0156), an exceptionally potent and selective inhibitor of ATM based on an imidazo[4,5- c]quinolin-2-one core. 64 has good preclinical phamacokinetics, a low predicted clinical dose, and a high maximum absorbable dose. 64 has been shown to potentiate the efficacy of the approved drugs irinotecan and olaparib in disease relevant mouse models and is currently undergoing clinical evaluation with these agents.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Diseño de Fármacos , Piridinas/farmacocinética , Quinolinas/farmacocinética , Quinolonas/farmacología , Quinolonas/farmacocinética , Administración Oral , Proteínas de la Ataxia Telangiectasia Mutada/química , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Disponibilidad Biológica , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Conformación Proteica , Inhibidores de Proteínas Quinasas , Piridinas/administración & dosificación , Piridinas/química , Quinolinas/administración & dosificación , Quinolinas/química , Quinolonas/administración & dosificación , Quinolonas/química , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
Optimization of cellular lipophilic ligand efficiency (LLE) in a series of 2-anilino-pyrimidine IGF-1R kinase inhibitors led to the identification of novel 2-(pyrazol-4-ylamino)-pyrimidines with improved physicochemical properties. Replacement of the imidazo[1,2-a]pyridine group of the previously reported inhibitor 3 with the related pyrazolo[1,5-a]pyridine improved IGF-1R cellular potency. Substitution of the amino-pyrazole group was key to obtaining excellent kinase selectivity and pharmacokinetic parameters suitable for oral dosing, which led to the discovery of (2R)-1-[4-(4-{[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}-3,5-dimethyl-1H-pyrazol-1-yl)-1-piperidinyl]-2-hydroxy-1-propanone (AZD9362, 28), a novel, efficacious inhibitor of IGF-1R.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Administración Oral , Animales , Línea Celular , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Femenino , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Piridinas/síntesis química , Piridinas/química , Receptor IGF Tipo 1/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the ataxia telangiectasia mutated (ATM) kinase. From a modestly potent HTS hit (4), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}-3-quinolinecarboxamide (72) and 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(1S)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (74) as potent and highly selective ATM inhibitors with overall ADME properties suitable for oral administration. 72 and 74 constitute excellent oral tools to probe ATM inhibition in vivo. Efficacy in combination with the DSB-inducing agent irinotecan was observed in a disease relevant model.
Asunto(s)
Antineoplásicos/farmacología , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Quinolinas/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Quinolinas/administración & dosificación , Quinolinas/química , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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
[reaction: see text] Two new unsymmetrical 1,2,4,5-tetrazines, 3-methylsulfinyl-6-methylthio-1,2,4,5-tetrazine (4) and 3-(benzyloxycarbonyl)amino-6-methylsulfinyl-1,2,4,5-tetrazine (5), were prepared, and the scope of their participation in intermolecular inverse electron demand Diels-Alder reactions was defined. As anticipated, sulfoxides 4 and 5 (4 > 5) display a reactivity that is substantially greater than that of their corresponding sulfides (2 and 3), being derived from their enhanced electron-deficient character and resulting in a wider range of potential dienophile choices or the use of milder reaction conditions. The cycloaddition reactions were expectedly regioselective, typically producing a single cycloadduct, ensuring their synthetic utility, but both were found to proceed with a regioselectivity opposite what would be anticipated and complementary to that observed with 2 and 3.