RESUMEN
Continuing studies based on dihydroquinoline glucocorticoid receptor agonists lead to the discovery of a series of C4-oxime analogs. Representative compounds exhibited potent transrepression activity with minimal transactivation of phosphoenolpyruvate caboxykinase (PEPCK), a key protein in the gluconeogenesis pathway. These compounds represent promising leads in identifying GR agonists with high anti-inflammatory activity and attenuated potential for glucose elevation.
Asunto(s)
Carboxiliasas/metabolismo , Quinolinas/farmacología , Receptores de Glucocorticoides/agonistas , Activación Enzimática , Quinolinas/química , Relación Estructura-ActividadRESUMEN
Continuing studies on tetrahydroquinoline glucocorticoid receptor anti-inflammatory agents lead to the identification of several tetrahydroquinolin-3-yl carbamates that exhibited steroid-like activity in in vitro transrepression assays with reduced transactivation of phosphoenol pyruvate carboxykinase (PEPCK), a key enzyme in the gluconeogenesis pathway.
Asunto(s)
Carboxiliasas/metabolismo , Quinolinas/farmacología , Receptores de Glucocorticoides/agonistas , Activación EnzimáticaRESUMEN
Treatment of inflammation is often accomplished through the use of glucocorticoids. However, their use is limited by side effects. We have examined the activity of a novel glucocorticoid receptor ligand that binds the receptor efficiently and strongly represses inflammatory gene expression. This compound has potent antiinflammatory activity in vivo and represses the transcription of the inflammatory cytokine monocyte chemoattractant protein-1 and induces the antiinflammatory cytokine IL-10. The compound demonstrates differential gene regulation, compared with commonly prescribed glucocorticoids, effectively inducing some genes and repressing others in a manner different from the glucocorticoid prednisolone. The separation between the antiinflammatory effects of LGD-5552 and the side effects commonly associated with glucocorticoid treatment suggest that this molecule differs significantly from prednisolone and other steroids and may provide a safer therapeutic window for inflammatory conditions now commonly treated with steroidal glucocorticoids.
Asunto(s)
Antiinflamatorios/efectos adversos , Antiinflamatorios/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Benzopiranos/efectos adversos , Benzopiranos/uso terapéutico , Compuestos de Bencilideno/efectos adversos , Compuestos de Bencilideno/uso terapéutico , Receptores de Glucocorticoides/agonistas , Animales , Artritis Reumatoide/tratamiento farmacológico , Células Cultivadas , Evaluación Preclínica de Medicamentos , Humanos , Ligandos , Masculino , Modelos Biológicos , Prednisolona/efectos adversos , Prednisolona/uso terapéutico , Ratas , Ratas Endogámicas Lew , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Spodoptera , Especificidad por SustratoRESUMEN
Structure-activity relationship studies centered around 3'-substituted (Z)-5-(2'-(thienylmethylidene))1,2-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-f]quinolines are described. A series of highly potent and efficacious selective glucocorticoid receptor modulators were identified with in vitro activity comparable to dexamethasone. In vivo evaluation of these compounds utilizing a 28 day mouse tumor xenograft model demonstrated efficacy equal to dexamethasone in the reduction of tumor volume.
Asunto(s)
Antineoplásicos/síntesis química , Benzopiranos/síntesis química , Mieloma Múltiple/tratamiento farmacológico , Quinolinas/síntesis química , Receptores de Glucocorticoides/efectos de los fármacos , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Benzopiranos/química , Benzopiranos/farmacología , Unión Competitiva , Dexametasona/farmacología , Humanos , Ratones , Antagonistas de Receptores de Mineralocorticoides , Modelos Moleculares , Mieloma Múltiple/patología , Quinolinas/química , Quinolinas/farmacología , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Mineralocorticoides/agonistas , Estereoisomerismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Specific retinoid X receptor (RXR) agonists, such as LG100268 (LG268), and the thiazolidinedione (TZD) PPARgamma agonists, such as rosiglitazone, produce insulin sensitization in rodent models of insulin resistance and type 2 diabetes. In sharp contrast to the TZDs that produce significant increases in body weight gain, RXR agonists reduce body weight gain and food consumption. Unfortunately, RXR agonists also suppress the thyroid hormone axis and generally produce hypertriglyceridemia. Heterodimer-selective RXR modulators have been identified that, in rodents, retain the metabolic benefits of RXR agonists with reduced side effects. These modulators bind specifically to RXR with high affinity and are RXR homodimer partial agonists. Although RXR agonists activate many heterodimer partners, these modulators selectively activate RXR:PPARalpha and RXR:PPARgamma, but not RXR:RARalpha, RXR:LXRalpha, RXR:LXRbeta, or RXR:FXRalpha. We report the in vivo characterization of one RXR modulator, LG101506 (LG1506). In Zucker fatty (fa/fa) rats, LG1506 is a potent insulin sensitizer that also enhances the insulin-sensitizing activities of rosiglitazone. Administration of LG1506 reduces both body weight gain and food consumption and blocks the TZD-induced weight gain when coadministered with rosiglitazone. LG1506 does not significantly suppress the thyroid hormone axis in rats, nor does it elevate triglycerides in Sprague Dawley rats. However, LG1506 produces a unique pattern of triglycerides elevation in Zucker rats. LG1506 elevates high-density lipoprotein cholesterol in humanized apolipoprotein A-1-transgenic mice. Therefore, selective RXR modulators are a promising approach for developing improved therapies for type 2 diabetes, although additional studies are needed to understand the strain-specific effects on triglycerides.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ácidos Grasos Insaturados/administración & dosificación , Hipoglucemiantes/administración & dosificación , Obesidad/tratamiento farmacológico , Éteres Fenílicos/administración & dosificación , Receptores X Retinoide/agonistas , Tiazolidinedionas/administración & dosificación , Análisis de Varianza , Animales , Apolipoproteína A-I/genética , Apolipoproteína A-I/fisiología , Área Bajo la Curva , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Hipoglucemiantes/uso terapéutico , Ratones , Ratones Transgénicos , Obesidad/sangre , Obesidad/complicaciones , PPAR gamma/agonistas , PPAR gamma/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Receptores X Retinoide/metabolismo , Rosiglitazona , Estadísticas no Paramétricas , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéutico , Glándula Tiroides/efectos de los fármacos , Triglicéridos/sangreRESUMEN
LSN862 is a novel peroxisome proliferator-activated receptor (PPAR)alpha/gamma dual agonist with a unique in vitro profile that shows improvements on glucose and lipid levels in rodent models of type 2 diabetes and dyslipidemia. Data from in vitro binding, cotransfection, and cofactor recruitment assays characterize LSN862 as a high-affinity PPARgamma partial agonist with relatively less but significant PPARalpha agonist activity. Using these same assays, rosiglitazone was characterized as a high-affinity PPARgamma full agonist with no PPARalpha activity. When administered to Zucker diabetic fatty rats, LSN862 displayed significant glucose and triglyceride lowering and a significantly greater increase in adiponectin levels compared with rosiglitazone. Expression of genes involved in metabolic pathways in the liver and in two fat depots from compound-treated Zucker diabetic fatty rats was evaluated. Only LSN862 significantly elevated mRNA levels of pyruvate dehydrogenase kinase isozyme 4 and bifunctional enzyme in the liver and lipoprotein lipase in both fat depots. In contrast, both LSN862 and rosiglitazone decreased phosphoenol pyruvate carboxykinase in the liver and increased malic enzyme mRNA levels in the fat. In addition, LSN862 was examined in a second rodent model of type 2 diabetes, db/db mice. In this study, LSN862 demonstrated statistically better antidiabetic efficacy compared with rosiglitazone with an equivalent side effect profile. LSN862, rosiglitazone, and fenofibrate were each evaluated in the humanized apoA1 transgenic mouse. At the highest dose administered, LSN862 and fenofibrate reduced very low-density lipoprotein cholesterol, whereas, rosiglitazone increased very low-density lipoprotein cholesterol. LSN862, fenofibrate, and rosiglitazone produced maximal increases in high-density lipoprotein cholesterol of 65, 54, and 30%, respectively. These findings show that PPARgamma full agonist activity is not necessary to achieve potent and efficacious insulin-sensitizing benefits and demonstrate the therapeutic advantages of a PPARalpha/gamma dual agonist.
Asunto(s)
Alquinos/farmacología , Cinamatos/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hiperlipidemias/tratamiento farmacológico , PPAR alfa/agonistas , PPAR alfa/metabolismo , PPAR gamma/agonistas , PPAR gamma/metabolismo , Adiponectina , Alquinos/química , Animales , Unión Competitiva , Peso Corporal , Colesterol/metabolismo , HDL-Colesterol/metabolismo , VLDL-Colesterol/metabolismo , Cinamatos/química , Diabetes Mellitus Tipo 2/metabolismo , Relación Dosis-Respuesta a Droga , Fenofibrato/farmacología , Regulación Enzimológica de la Expresión Génica , Glucosa/metabolismo , Homocigoto , Humanos , Hiperlipidemias/metabolismo , Técnicas In Vitro , Insulina/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Cinética , Metabolismo de los Lípidos , Hígado/enzimología , Masculino , Ratones , Ratones Transgénicos , Modelos Químicos , Unión Proteica , Isoformas de Proteínas , ARN Mensajero/metabolismo , Ratas , Rosiglitazona , Tiazolidinedionas/farmacología , Transfección , Triglicéridos/metabolismo , Técnicas del Sistema de Dos HíbridosRESUMEN
Nuclear receptors (NRs) are a superfamily of ligand-dependent transcription factors that control diverse aspects of growth, development and homeostasis, making them exciting and important targets for drug discovery. In this review, some of the recent advances in our understanding of NRs, and their application to the discovery of new ligands, will be discussed.
Asunto(s)
Farmacología/métodos , Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Animales , Evaluación Preclínica de Medicamentos , Expresión Génica , Humanos , LigandosRESUMEN
Retinoid X receptor:peroxisome proliferative-activated receptor (RXR:PPAR) heterodimers play a critical role in the regulation of glucose (RXR/PPARgamma) and lipid metabolism (RXR/PPARalpha). Previously, we described a concise structure-activity relationship study of selective RXR modulators possessing a (2E,4E,6Z)-3-methyl-7-(3,5-dialkyl-6-alkoxyphenyl)-octa-2,4,6-trienoic acid scaffold. These studies were focused on the 2-position alkoxy side chain. We describe here the design and synthesis of a novel series of RXR selective modulators possessing the same aromatic core structure with the addition of a ring locked 6-7-Z-olefin on the trienoic acid moiety. The synthesis and structure-activity relationship studies of these 6,7-locked cyclopentenyl, phenyl, thienyl, furan, and pyridine-trienoic acid derivatives is presented herein.
Asunto(s)
Derivados del Benceno/química , Derivados del Benceno/farmacología , Caprilatos/química , Caprilatos/farmacología , Tiazolidinedionas , Alquenos/química , Alquenos/farmacología , Animales , Derivados del Benceno/síntesis química , Caprilatos/síntesis química , Línea Celular , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Sinergismo Farmacológico , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Masculino , Ratones , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Ácido Retinoico/agonistas , Receptores de Ácido Retinoico/antagonistas & inhibidores , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Receptores X Retinoide , Rosiglitazona , Relación Estructura-Actividad , Tiazoles/farmacología , Tiroxina/sangre , Factores de Transcripción/agonistas , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transfección , Triglicéridos/sangreRESUMEN
A new series of hPPARalpha agonists containing a 2,4-dihydro-3H-1,2,4-triazol-3-one (triazolone) core is described leading to the discovery of 5 (LY518674), a highly potent and selective PPARalpha agonist.
Asunto(s)
Propionatos/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Triazoles/síntesis química , Administración Oral , Animales , Apolipoproteína A-I/genética , Unión Competitiva , Disponibilidad Biológica , Línea Celular , Perros , Diseño de Fármacos , Humanos , Ratones , Ratones Transgénicos , Propionatos/química , Propionatos/farmacología , Ensayo de Unión Radioligante , Ratas , Relación Estructura-Actividad , Factores de Transcripción/metabolismo , Transfección , Triazoles/química , Triazoles/farmacologíaRESUMEN
The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR alpha/gamma agonist profile (IC(50) = 28 and 10 nM; EC(50) = 9 and 4 nM, respectively, for hPPARalpha and hPPARgamma). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.
Asunto(s)
Hipoglucemiantes/síntesis química , Hipolipemiantes/síntesis química , Fenilpropionatos/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Tiofenos/síntesis química , Factores de Transcripción/agonistas , Animales , Unión Competitiva , Línea Celular , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Humanos , Hiperlipidemias/tratamiento farmacológico , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Hipolipemiantes/química , Hipolipemiantes/farmacología , Fenilpropionatos/química , Fenilpropionatos/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Zucker , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacologíaRESUMEN
The synthesis and in vitro characterization of novel RXR-selective ligands possessing various substituted 1-benzofuran or 1-benzothiophene moieties are described.
Asunto(s)
Diseño de Fármacos , Receptores de Ácido Retinoico/metabolismo , Factores de Transcripción/metabolismo , Tretinoina/análogos & derivados , Tretinoina/metabolismo , Unión Proteica/fisiología , Receptores X Retinoide , Relación Estructura-ActividadRESUMEN
New RXR-selective modulators possessing a 6-fluoro trienoic acid moiety (6Z olefin) or a fluorinated/heterocyclic-substituted benzene core ring, were synthesized in an expedient and selective way. A subset of these compounds was evaluated for their metabolic properties (exposure in IRC male mice) and show a dramatic increase of exposure compared to our reference compound, 3 (LG101506).
Asunto(s)
Cumarinas/síntesis química , Cumarinas/farmacología , Receptores de Ácido Retinoico/fisiología , Factores de Transcripción/fisiología , Animales , Unión Competitiva , Línea Celular , Diseño de Fármacos , Cinética , Masculino , Ratones , Receptores de Ácido Retinoico/efectos de los fármacos , Receptor alfa de Ácido Retinoico , Receptores X Retinoide , Factores de Transcripción/efectos de los fármacos , Tretinoina/farmacocinética , Receptor de Ácido Retinoico gammaRESUMEN
To understand the species selectivity in a series of alpha-methyl-alpha-phenoxy carboxylic acid PPARalpha/gamma dual agonists (1-11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARalpha. This study suggested that interaction of both 4-phenoxy and phenyloxazole substituents of these ligands with F272 and M279 in mouse PPARalpha leads to the species-specific divergence in ligand binding. Insights obtained in the molecular modeling studies of these key interactions resulted in the ability to convert a human-selective PPARalpha agonist to a human and mouse dual agonist within the same platform.