RESUMEN
The design, synthesis and biological evaluation of a series of azabenzimidazole derivatives as TBK1/IKKε kinase inhibitors are described. Starting from a lead compound 1a, iterative design and SAR exploitation of the scaffold led to analogues with nM enzyme potencies against TBK1/IKKε. These compounds also exhibited excellent cellular activity against TBK1. Further structure-based design to improve selectivity over CDK2 and Aurora B resulted in compounds such as 5b-e. These probe compounds will facilitate study of the complex cancer biology of TBK1 and IKKε.
Asunto(s)
Bencimidazoles/química , Bencimidazoles/farmacología , Quinasa I-kappa B/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Aurora Quinasa B , Aurora Quinasas , Compuestos Aza/química , Compuestos Aza/farmacología , Quinasa 2 Dependiente de la Ciclina/metabolismo , Diseño de Fármacos , Células HEK293 , Humanos , Quinasa I-kappa B/metabolismo , Modelos Moleculares , Neoplasias/enzimología , Proteínas Serina-Treonina Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
Structure-activity relationship analysis identified (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), from a series of novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.
Asunto(s)
Antineoplásicos/síntesis química , Benzamidas/síntesis química , Cinesinas/antagonistas & inhibidores , Pirimidinonas/síntesis química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Benzamidas/farmacocinética , Benzamidas/farmacología , Proteínas Sanguíneas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Hepatocitos/metabolismo , Humanos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Ratones , Ratones Desnudos , Microsomas Hepáticos/metabolismo , Unión Proteica , Pirimidinonas/farmacocinética , Pirimidinonas/farmacología , Ratas , Ratas Wistar , Solubilidad , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Synthesis and biological evaluation of a series of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors was reported. Biochemical screening, followed by profile optimization, resulted in JAK2 inhibitors exhibiting good kinase selectivity, pharmacokinetic properties, physical properties and pharmacodynamic effects.
Asunto(s)
Janus Quinasa 2/antagonistas & inhibidores , Nitrilos/síntesis química , Nitrilos/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/química , Piridinas/química , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Nitrilos/química , Nitrilos/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are a heterogeneous but related group of hematological malignancies characterized by clonal expansion of one or more myeloid lineages. The discovery of the Jak2 V617F gain of function mutation highlighted Jak2 as a potential therapeutic target in the MPNs. Herein, we disclose the discovery of a series of pyrazol-3-yl pyrimidin-4-amines and the identification of 9e (AZD1480) as a potent Jak2 inhibitor. 9e inhibits signaling and proliferation of Jak2 V617F cell lines in vitro, demonstrates in vivo efficacy in a TEL-Jak2 model, has excellent physical properties and preclinical pharmacokinetics, and is currently being evaluated in Phase I clinical trials.
Asunto(s)
Janus Quinasa 2/antagonistas & inhibidores , Pirazoles/síntesis química , Pirimidinas/síntesis química , Factores de Transcripción STAT/fisiología , Animales , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Femenino , Humanos , Técnicas In Vitro , Janus Quinasa 2/química , Ratones , Ratones Desnudos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Fosforilación , Conformación Proteica , Pirazoles/farmacocinética , Pirazoles/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Factores de Transcripción STAT/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT5/metabolismo , Transducción de Señal , Estereoisomerismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The design, synthesis and biological evaluation of a series of pyrazol-3-ylamino pyrazines as potent and selective JAK2 kinase inhibitors is reported, along with the pharmacokinetic and pharmacodynamic properties of lead compounds.
Asunto(s)
Descubrimiento de Drogas , Janus Quinasa 2/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/farmacología , Pirazoles/farmacología , Animales , Perros , Humanos , Ratones , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazinas/síntesis química , Pirazinas/química , Pirazoles/síntesis química , Pirazoles/química , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
3-amido-4-anilinoquinolines are potent and highly selective inhibitors of CSF-1R. Their synthesis and SAR is reported, along with initial efforts to optimize the physical properties and PK through modifications at the quinoline 6- and 7-positions.
Asunto(s)
Química Farmacéutica/métodos , Neoplasias/tratamiento farmacológico , Quinolinas/química , Quinolinas/farmacocinética , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Receptor de Factor Estimulante de Colonias de Macrófagos/química , Administración Oral , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , RatasRESUMEN
The design, synthesis and biological evaluation of a series of 4-aminopyrazolylpyrimidines as potent Trk kinase inhibitors is reported. High-throughput screening identified a promising hit in the 4-aminopyrazolylpyrimidine chemotype. Initial optimization of the series led to more potent Trk inhibitors. Further optimization using two strategies resulted in significant improvement of physical properties and led to the discovery of 10z (AZ-23), a potent, orally bioavailable Trk A/B inhibitor. The compound offers the potential to test the hypothesis that modulation of Trk activity will be of benefit in the treatment of cancer and other indications in vivo.
Asunto(s)
Aminas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/farmacología , Receptor trkA/antagonistas & inhibidores , Animales , Línea Celular , Humanos , Masculino , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Ratas , Ratas Wistar , Receptor trkA/química , Receptor trkA/metabolismo , Relación Estructura-ActividadRESUMEN
The interaction of co-stimulatory molecules on T cells with B7 molecules on antigen presenting cells plays an important role in the activation of naive T cells. Consequently, agents that disrupt these interactions should have applications in treatment of transplant rejection as well as autoimmune diseases. To this end, specific small molecule inhibitors of human B7.1 were identified and characterized. Herein, we report the identification of potent small molecule inhibitors of the B7.1-CD28 interaction. In a high-throughput screen we identified several leads that prevented the interaction of B7.1 with CD28 with activities in the nanomolar to low micromolar range. One of these, the dihydrodipyrazolopyridinone 1, was subsequently shown to bind the V-like domain of human B7.1 at equimolar stoichiometry. With this as a starting point, we report here the synthesis and initial in vitro structure-activity relationships of a series of these compounds.