RESUMEN
A series of nonsteroidal human androgen receptor (hAR) antagonists based on 8-substituted 1,2-dihydro- and 1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethylpyrido[3,2-g]quin olines was synthesized. Compounds in this series were tested for the ability to bind to hAR and inhibit hAR-dependent transcription in a mammalian cellular background.
Asunto(s)
Antagonistas de Andrógenos/síntesis química , Antagonistas de Receptores Androgénicos , Piridonas/química , Piridonas/síntesis química , Quinolinas/síntesis química , Antagonistas de Andrógenos/farmacología , Andrógenos/metabolismo , Animales , Células COS , Humanos , Piridonas/farmacología , Quinolinas/farmacología , Transcripción Genética/efectos de los fármacosRESUMEN
A series of human androgen receptor (hAR) agonists based on 4-alkyl-; 4,4-dialkyl-; and 3,4-dialkyl-1,2,3,4-tetrahydro-8-pyridono[5,6-g]quinoline was synthesized and evaluated in competitive receptor binding assays and an androgen receptor cotransfection assay in a mammalian cell background. A number of compounds in this series demonstrated activity equal to or better than dihydrotestosterone in both assays and represent a novel class of compounds for use in androgen replacement therapy.
Asunto(s)
Andrógenos , Quinolonas/síntesis química , Quinolonas/farmacología , Animales , Células COS , Dihidrotestosterona/farmacología , Humanos , Concentración 50 Inhibidora , Cinética , Unión ProteicaRESUMEN
A series of 2H-pyrano[3,2-g]quinolin-2-ones was prepared and tested for the ability to modulate the transcriptional activity of the human androgen receptor (hAR). The parent compound, 4-(trifluoromethyl)-2H-pyrano[3,2-g]quinolin-2-one, displayed moderate interaction with hAR, but substituted analogues were potent hAR modulators in vitro as measured by an hAR cotransfection assay in CV-1 cells and bound to hAR with high affinity in a whole cell assay. Several analogues were able to activate hAR-mediated gene transcription more potently and efficaciously than dihydrotestosterone.
Asunto(s)
Andrógenos , Benzopiranos/química , Benzopiranos/farmacología , Quinolonas/química , Quinolonas/farmacología , Animales , Células COS , Línea Celular , Humanos , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Relación Estructura-Actividad , Transcripción Genética/efectos de los fármacos , TransfecciónAsunto(s)
Andrógenos , Piridinas/química , Quinolonas/química , Administración Oral , Animales , Células COS , Humanos , Masculino , Estructura Molecular , Piridinas/administración & dosificación , Piridinas/farmacología , Quinolonas/administración & dosificación , Quinolonas/farmacología , Ratas , TransfecciónRESUMEN
A new nonsteroidal antiandrogenic pharmacophore has been discovered using cell-based cotransfection assays with human androgen receptor (hAR). This series of AR antagonists is structurally characterized by a linear tricyclic 1,2-dihydropyridono[5,6-g]quinoline core. Analogues inhibit AR-mediated reporter gene expression and bind to AR as potently as or better than any known AR antagonists. Several analogues also showed excellent in vivo activity in classic rodent models of AR antagonism, inhibiting growth of rat ventral prostate and seminal vesicles, without accompanying increases in serum gonadotropin and testosterone levels, as is seen with other AR antagonists. Investigations of structure-activity relationships surrounding this pharmacophore resulted in molecules with complete specificity for AR, antagonist activity on an AR mutant commonly observed in prostate cancer patients, and improved in vivo efficacy. Molecules based on this series of compounds have the potential to provide unique and effective clinical opportunities for treatment of prostate cancer and other androgen-dependent diseases.
Asunto(s)
Antagonistas de Andrógenos/síntesis química , Dihidropiridinas/síntesis química , Compuestos Heterocíclicos/síntesis química , Quinolinas/síntesis química , Receptores Androgénicos/metabolismo , Antagonistas de Andrógenos/química , Antagonistas de Andrógenos/farmacología , Antagonistas de Receptores Androgénicos , Animales , Células COS , Línea Celular , Dihidropiridinas/química , Dihidropiridinas/farmacología , Dihidrotestosterona/farmacología , Gonadotropinas/sangre , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacocinética , Humanos , Indicadores y Reactivos , Masculino , Estructura Molecular , Orquiectomía , Próstata/efectos de los fármacos , Próstata/crecimiento & desarrollo , Quinolinas/química , Quinolinas/farmacocinética , Quinolinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Progesterona/biosíntesis , Receptores de Progesterona/metabolismo , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/metabolismo , Vesículas Seminales/efectos de los fármacos , Vesículas Seminales/crecimiento & desarrollo , Relación Estructura-Actividad , Testosterona/sangre , TransfecciónRESUMEN
A series of nonsteroidal human progesterone receptor (hPR) antagonists based on conformationally-restricted analogues of a 6-aryl-1,2-dihydro-2,2,4-trimethylquinoline pharmacophore were synthesized and evaluated for their ability to bind to the human progesterone receptor and inhibit progesterone-stimulated reporter gene expression in mammalian cells.
Asunto(s)
Quinolinas/química , Quinolinas/farmacología , Receptores de Progesterona/antagonistas & inhibidores , Humanos , Conformación Molecular , Relación Estructura-ActividadRESUMEN
Retinoic acid receptors (RAR), thyroid hormone receptors (TR), peroxisome proliferator activated receptors (PPARs) and the orphan receptor, LXR, bind preferentially to DNA as heterodimers with a common partner, retinoid X receptor (RXR), to regulate transcription. We investigated whether RXR-selective agonists replicate the activity of ligands for several of these receptors? We demonstrate here that RXR-selective ligands (referred to as rexinoids) function as RXR heterodimer-selective agonists, activating RXR: PPARgamma and RXR:LXR dimers but not RXR:RAR or RXR:TR heterodimers. Because PPARgamma is a target for antidiabetic agents, we investigated whether RXR ligands could alter insulin and glucose signalling. In mouse models of noninsulin-dependent diabetes mellitus (NIDDM) and obesity, RXR agonists function as insulin sensitizers and can decrease hyperglycaemia, hypertriglyceridaemia and hyperinsulinaemia. This antidiabetic activity can be further enhanced by combination treatment with PPARgamma agonists, such as thiazolidinediones. These data suggest that the RXR:PPARgamma heterodimer is a single-function complex serving as a molecular target for treatment of insulin resistance. Activation of the RXR:PPARgamma dimer with rexinoids may provide a new and effective treatment for NIDDM.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Resistencia a la Insulina , Insulina/farmacología , Obesidad/metabolismo , Receptores de Ácido Retinoico/agonistas , Tiazolidinedionas , Factores de Transcripción/agonistas , Animales , Bexaroteno , Glucemia/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/sangre , Femenino , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes/farmacología , Insulina/sangre , Ligandos , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Ácidos Nicotínicos/farmacología , Obesidad/sangre , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Receptores X Retinoide , Rosiglitazona , Tetrahidronaftalenos/farmacología , Tiazoles/farmacología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , TransfecciónRESUMEN
The ob gene product, leptin, is a signaling factor regulating body weight and energy balance. ob gene expression in rodents is increased in obesity and is regulated by feeding patterns and hormones, such as insulin and glucocorticoids. In humans with gross obesity, ob mRNA levels are higher, but other modulators of human ob expression are unknown. In view of the importance of peroxisome proliferator-activated receptor gamma (PPARgamma) in adipocyte differentiation, we analyzed whether ob gene expression is subject to regulation by factors activating PPARs. Treatment of rats with the PPARalpha activator fenofibrate did not change adipose tissue and body weight and had no significant effect on ob mRNA levels. However, administration of the thiazolidinedione BRL49653, a PPARgamma ligand, increased food intake and adipose tissue weight while reducing ob mRNA levels in rats in a dose-dependent manner. The inhibitory action of the thiazolidinedione BRL49653 on ob mRNA levels was also observed in vitro. Thiazolidinediones reduced the expression of the human ob promoter in primary adipocytes, however, in undifferentiated 3T3-L1 preadipocytes lacking endogenous PPARgamma, cotransfection of PPARgamma was required to observe the decrease. In conclusion, these data suggest that PPARgamma activators reduce ob mRNA levels through an effect of PPARgamma on the ob promoter.
Asunto(s)
Proteínas/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Tiazoles/farmacología , Tiazolidinedionas , Factores de Transcripción/metabolismo , Adipocitos/metabolismo , Tejido Adiposo/anatomía & histología , Tejido Adiposo/metabolismo , Animales , Secuencia de Bases , Cartilla de ADN/química , Activación Enzimática , Expresión Génica/efectos de los fármacos , Humanos , Leptina , Hígado/anatomía & histología , Datos de Secuencia Molecular , Tamaño de los Órganos/efectos de los fármacos , Pioglitazona , Regiones Promotoras Genéticas , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Receptores Citoplasmáticos y Nucleares/agonistas , Rosiglitazona , Factores de Transcripción/agonistasRESUMEN
A novel class of nonsteroidal progesterone receptor antagonists has been synthesized and was shown to exhibit moderate binding affinity for hPR-A, the ability to inhibit the transcriptional activity of human progesterone receptor (hPR) in cell-based assays, and anti-progestational activity in a murine model. Cyclocymopol monomethyl ether, a component of the marine alga Cymopolia barbata was weakly active in random screening against PR. Investigations into the SAR surrounding the core of this natural product lead structure resulted in improved in vitro activity. In contrast to the cross-reactivity profiles observed with known steroidal antiprogestins, compounds of the general structural class described display a high degree of selectivity for the progesterone receptor and no functional activity on the glucocorticoid receptor.
Asunto(s)
Anisoles/farmacología , Ciclohexanos/síntesis química , Ciclohexanos/farmacología , Receptores de Progesterona/antagonistas & inhibidores , Animales , Línea Celular , Ciclohexanos/química , Ciclohexenos , Femenino , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Utilizing the co-transfection assay as a guide to determining structure activity relationships, we have been pursuing the discovery of non-steroidal hPR modulators. Small molecule, non-steroidal lead structures have been identified. Optimization of these structures has yielded more potent hPR modulators. Improved cross-reactivity profiles with other intracellular receptors are a feature of these compounds owing to their non-steroidal nature.