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
A novel series of quinoline isoxazole BET family bromodomain inhibitors are discussed. Crystallography is used to illustrate binding modes and rationalize their SAR. One member, I-BET151 (GSK1210151A), shows good oral bioavailability in both the rat and minipig as well as demonstrating efficient suppression of bacterial induced inflammation and sepsis in a murine in vivo endotoxaemia model.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/química , Isoxazoles/síntesis química , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Quinolinas/síntesis química , Animales , Sitios de Unión , Cristalografía por Rayos X , Cobayas , Compuestos Heterocíclicos de 4 o más Anillos/metabolismo , Inflamación/tratamiento farmacológico , Isoxazoles/química , Isoxazoles/farmacología , Ratones , Modelos Moleculares , Unión Proteica/efectos de los fármacos , Quinolinas/química , Quinolinas/farmacología , RatasRESUMEN
RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteínas de Complejo Poro Nuclear/antagonistas & inhibidores , Pirazoles/síntesis química , Pirazoles/farmacología , Proteínas de Unión al ARN/antagonistas & inhibidores , Animales , Disponibilidad Biológica , Línea Celular , Enfermedad Crónica , Diseño de Fármacos , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Inhibidores Enzimáticos/farmacocinética , Haplorrinos , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Esclerosis Múltiple/tratamiento farmacológico , Pirazoles/farmacocinética , Ratas , Retinitis Pigmentosa/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
We describe the discovery of novel potent inhibitors of 2,3-oxidosqualene:lanosterol cyclase inhibitors (OSCi) from a focused pharmacophore-based screen. Optimization of the most tractable hits gave a series of compounds showing inhibition of cholesterol biosynthesis at 2mg/kg in the rat with distinct pharmacokinetic profiles. Two compounds were selected for toxicological study in the rat for 21 days in order to test the hypothesis that low systemic exposure could be used as a strategy to avoid the ocular side effects previously described with OSCi. We demonstrate that for this series of inhibitors, a reduction of systemic exposure is not sufficient to circumvent cataract liabilities.
Asunto(s)
Catarata/enzimología , Dislipidemias/enzimología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Ojo/efectos de los fármacos , Transferasas Intramoleculares/antagonistas & inhibidores , Animales , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/farmacocinética , Catarata/inducido químicamente , Catarata/tratamiento farmacológico , Línea Celular Tumoral , Dislipidemias/inducido químicamente , Inhibidores Enzimáticos/efectos adversos , Ojo/metabolismo , Femenino , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Oxazoles/farmacocinética , Oxazoles/uso terapéutico , Piperazinas/efectos adversos , Piperazinas/síntesis química , Piperazinas/farmacocinética , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
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
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.