RESUMEN
Decreased erythropoietin (EPO) production, shortened erythrocyte survival, and other factors reducing the response to EPO contribute to anemia in patients who have a variety of underlying pathologies such as chronic kidney disease. Treatment with recombinant human EPO (rHuEPO) at supraphysiologic concentrations has proven to be efficacious. However, it does not ameliorate the condition in all patients, and it presents its own risks, including cardiovascular complications. The transcription factors hypoxia-inducible factor (HIF) 1α and HIF2α control the physiologic response to hypoxia and invoke a program of increased erythropoiesis. Levels of HIFα are modulated by oxygen tension via the action of a family of HIF-prolyl hydroxylases (PHDs), which tag HIFα for proteasomal degradation. Inhibition of these PHDs simulates conditions of mild hypoxia, leading to a potentially more physiologic erythropoietic response and presenting a potential alternative to high doses of rHuEPO. Here we describe the discovery and characterization of GSK1278863 [2-(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido) acetic acid], a pyrimidinetrione-glycinamide low nanomolar inhibitor of PHDs 1-3 that stabilizes HIFα in cell lines, resulting in the production of increased levels of EPO. In normal mice, a single dose of GSK1278863 induced significant increases in circulating plasma EPO but only minimal increases in plasma vascular endothelial growth factor (VEGF-A) concentrations. GSK1278863 significantly increased reticulocytes and red cell mass parameters in preclinical species after once-daily oral administration and has demonstrated an acceptable nonclinical toxicity profile, supporting continued clinical development. GSK1278863 is currently in phase 3 clinical trials for treatment of anemia in patients with chronic kidney disease.
Asunto(s)
Barbitúricos/farmacología , Drogas en Investigación/farmacología , Inhibidores Enzimáticos/farmacología , Eritropoyesis/efectos de los fármacos , Eritropoyetina/agonistas , Glicina/análogos & derivados , Hematínicos/farmacología , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Animales , Barbitúricos/administración & dosificación , Barbitúricos/efectos adversos , Barbitúricos/farmacocinética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/agonistas , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/química , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Línea Celular Tumoral , Perros , Relación Dosis-Respuesta a Droga , Drogas en Investigación/administración & dosificación , Drogas en Investigación/efectos adversos , Drogas en Investigación/farmacocinética , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Eritropoyetina/genética , Eritropoyetina/metabolismo , Femenino , Glicina/administración & dosificación , Glicina/efectos adversos , Glicina/farmacocinética , Glicina/farmacología , Hematínicos/administración & dosificación , Hematínicos/efectos adversos , Hematínicos/farmacocinética , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/agonistas , Subunidad alfa del Factor 1 Inducible por Hipoxia/química , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Ratones , Estabilidad Proteica/efectos de los fármacos , Ratas Sprague-Dawley , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Pruebas de Toxicidad CrónicaRESUMEN
Inhibition of mitotic kinesins represents a novel approach for the discovery of a new generation of anti-mitotic cancer chemotherapeutics. We report here the discovery of the first potent and selective inhibitor of centromere-associated protein E (CENP-E) 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide (GSK923295; 1), starting from a high-throughput screening hit, 3-chloro-4-isopropoxybenzoic acid 2. Compound 1 has demonstrated broad antitumor activity in vivo and is currently in human clinical trials.
RESUMEN
The synthesis and optimisation of HCV NS5B polymerase inhibitors with improved potency versus the existing compound 1 is described. Substitution in the benzothiadiazine portion of the molecule, furnishing improvement in potency in the high protein Replicon assay, is highlighted, culminating in the discovery of 12h, a highly potent oxyacetamide derivative.
Asunto(s)
Antivirales/síntesis química , Benzotiadiazinas/química , Química Farmacéutica/métodos , Hepacivirus/enzimología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Antivirales/farmacología , Benzotiadiazinas/farmacología , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
Modification of the benzo rings of 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones into heteroaromatic systems was investigated to enhance physicochemical properties and potency profile of this class of inhibitors. The synthesis and biological activity of the derived compounds is discussed.
Asunto(s)
Química Farmacéutica/métodos , Quinolonas/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/síntesis química , Antivirales/farmacología , Diseño de Fármacos , Genotipo , Hepacivirus/metabolismo , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Estructura Molecular , Unión Proteica , Quinolonas/farmacología , Relación Estructura-ActividadRESUMEN
Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.
Asunto(s)
Antivirales/síntesis química , Benzotiadiazinas/síntesis química , Hepacivirus/enzimología , Quinolonas/síntesis química , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Tiadiazinas/síntesis química , Animales , Antivirales/química , Antivirales/farmacología , Benzotiadiazinas/química , Benzotiadiazinas/farmacología , Disponibilidad Biológica , Proteínas Sanguíneas/metabolismo , Línea Celular , Cristalografía por Rayos X , Perros , Genotipo , Semivida , Hepacivirus/genética , Macaca fascicularis , Modelos Moleculares , Estructura Molecular , Mutación , Unión Proteica , Quinolonas/química , Quinolonas/farmacología , ARN Polimerasa Dependiente del ARN/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiadiazinas/química , Tiadiazinas/farmacologíaRESUMEN
[reaction: see text] An efficient two-pot, asymmetric synthesis of benzothiadiazine-substituted tetramic acids is reported. Starting from commercially available alpha-amino acids or esters, reductive amination followed by a novel one-pot amide bond formation/Dieckmann cyclization provided the desired products in high yield and optical purity. An analogous solid-phase approach to the same targets is also presented. These compounds were found to be potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase.