RESUMEN
The discovery, synthesis and biological evaluation of a novel series of 7-isoxazoloquinolines is described. Several analogs are shown to increase ApoA1 expression within the nanomolar range in the human hepatic cell line HepG2.
Asunto(s)
Apolipoproteína A-I/metabolismo , Descubrimiento de Drogas , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Proteínas Nucleares/antagonistas & inhibidores , Quinolinas/química , Regulación hacia Arriba/efectos de los fármacos , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Células Hep G2 , Histona Acetiltransferasas , Chaperonas de Histonas , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos BALB C , Proteínas del Tejido Nervioso , Proteínas Nucleares/metabolismo , Quinolinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Lactamas/farmacología , 1-Alquil-2-acetilglicerofosfocolina Esterasa , Administración Oral , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Perros , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Lactamas/administración & dosificación , Lactamas/síntesis química , Lactamas/química , Modelos Moleculares , Estructura Molecular , Ratas , Relación Estructura-Actividad , Distribución TisularRESUMEN
Bromodomains (BRDs) are small protein domains found in a variety of proteins that recognize and bind to acetylated histone tails. This binding affects chromatin structure and facilitates the localisation of transcriptional complexes to specific genes, thereby regulating epigenetically controlled processes including gene transcription and mRNA elongation. Inhibitors of the bromodomain and extra-terminal (BET) proteins BRD2-4 and T, which prevent bromodomain binding to acetyl-modified histone tails, have shown therapeutic promise in several diseases. We report here the discovery of 1,5-naphthyridine derivatives as potent inhibitors of the BET bromodomain family with good cell activity and oral pharmacokinetic parameters. X-ray crystal structures of naphthyridine isomers have been solved and quantum mechanical calculations have been used to explain the higher affinity of the 1,5-isomer over the others. The best compounds were progressed in a mouse model of inflammation and exhibited dose-dependent anti-inflammatory pharmacology.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Naftiridinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Proteínas Cromosómicas no Histona , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Histonas/química , Histonas/metabolismo , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Naftiridinas/química , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína/efectos de los fármacos , Relación Estructura-Actividad , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismoRESUMEN
AMP-activated protein kinase (AMPK) is an evolutionarily conserved fuel-sensing enzyme that is activated in shortage of energy and suppressed in its surfeit. AMPK activation stimulates fatty acid oxidation, enhances insulin sensitivity, alleviates hyperglycemia and hyperlipidemia, and inhibits proinflammatory changes. Thus, AMPK is a well-received therapeutic target for type 2 diabetes and other metabolic disorders. Here, we will report the discovery of pyrrolopyridone derivatives as AMPK direct activators. We will illustrate the synthesis and structure-activity relationships of the series as well as some pharmacokinetic results. Some compounds exhibited encouraging oral exposure and were evaluated in a mouse diabetic model. Compound 17 showed oral activity at 30 mg/kg on blood glucose.