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
The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and PPARdelta are ligand-activated transcription factors that play a key role in lipid homeostasis. The fibrates raise circulating levels of high-density lipoprotein cholesterol and lower levels of triglycerides in part through their activity as PPARalpha agonists; however, the low potency and restricted selectivity of the fibrates may limit their efficacy, and it would be desirable to develop more potent and selective PPARalpha agonists. Modification of the selective PPARdelta agonist 1 (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of the fibrates led to a marked shift in potency and selectivity toward PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 = 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials for the treatment of diseases of lipid imbalance.
Asunto(s)
HDL-Colesterol/sangre , PPAR alfa/agonistas , Propionatos/síntesis química , Tiazoles/síntesis química , Animales , Apolipoproteína A-I/genética , VLDL-Colesterol/sangre , Cristalografía por Rayos X , Perros , Dislipidemias/sangre , Dislipidemias/tratamiento farmacológico , Humanos , Ligandos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Moleculares , PPAR alfa/química , Propionatos/farmacocinética , Propionatos/farmacología , Estructura Terciaria de Proteína , Ratas , Ratas Wistar , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacología , Triglicéridos/sangreRESUMEN
Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.
Asunto(s)
Aminoquinolinas/síntesis química , Antiinflamatorios/síntesis química , Apolipoproteína A-I/metabolismo , Benzoatos/síntesis química , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Quinolinas/síntesis química , Factores de Transcripción/antagonistas & inhibidores , Aminoquinolinas/farmacocinética , Aminoquinolinas/farmacología , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Benzoatos/farmacocinética , Benzoatos/farmacología , Proteínas de Ciclo Celular , Descubrimiento de Drogas , Humanos , Ratones , Quinolinas/farmacocinética , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
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.
RESUMEN
The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers.
Asunto(s)
Antineoplásicos/farmacología , Benzodiazepinas/farmacología , Proteínas Nucleares/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Apolipoproteína A-I/biosíntesis , Benzodiazepinas/síntesis química , Benzodiazepinas/farmacocinética , Proteínas de Ciclo Celular , Perros , Epigénesis Genética , Humanos , Macaca fascicularis , Ratones , Modelos Moleculares , Permeabilidad , Estructura Terciaria de Proteína , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Epigenetic mechanisms of gene regulation have a profound role in normal development and disease processes. An integral part of this mechanism occurs through lysine acetylation of histone tails which are recognized by bromodomains. While the biological and structural characterization of many bromodomain containing proteins has advanced considerably, the therapeutic tractability of this protein family is only now becoming understood. This paper describes the discovery and molecular characterization of potent (nM) small molecule inhibitors that disrupt the function of the BET family of bromodomains (Brd2, Brd3, and Brd4). By using a combination of phenotypic screening, chemoproteomics, and biophysical studies, we have discovered that the protein-protein interactions between bromodomains and acetylated histones can be antagonized by selective small molecules that bind at the acetylated lysine recognition pocket. X-ray crystal structures of compounds bound into bromodomains of Brd2 and Brd4 elucidate the molecular interactions of binding and explain the precisely defined stereochemistry required for activity.