RESUMEN
A series of quinoline-3-carboxamide containing sulfones was prepared and found to have good binding affinity for LXRbeta and moderate binding selectivity over LXRalpha. The 8-Cl quinoline analog 33 with a high TPSA score, displayed 34-fold binding selectivity for LXRbeta over LXRalpha (LXRbeta IC(50)=16nM), good activity for inducing ABCA1 gene expression in a THP macrophage cell line, desired weak potency in the LXRalpha Gal4 functional assay, and low blood-brain barrier penetration in rat.
Asunto(s)
Barrera Hematoencefálica/metabolismo , Receptores Nucleares Huérfanos/agonistas , Quinolinas/química , Sulfonas/química , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Sitios de Unión , Línea Celular , Simulación por Computador , Humanos , Enlace de Hidrógeno , Receptores X del Hígado , Receptores Nucleares Huérfanos/metabolismo , Unión Proteica , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/farmacocinéticaRESUMEN
A series of cinnolines/quinolines was prepared and it was found that 4-phenyl-cinnoline/quinolines with either a 2',3' or 2',5'-disubstituted benzyloxy moiety or the 1-Me-7-indole methoxy moiety on the meta position of the 4-phenyl ring showed good binding selectivity for LXRbeta over LXRalpha. The LXRbeta binding selective modulators displayed good activity for inducing ABCA1 gene expression in J774 macrophage cell line and poor efficacy in the LXRalpha Gal4 functional assay. 26, 37 and 41 were examined for their ability to induce SREBP-1c gene expression in Huh-7 liver cell line and they were weak partial agonists.
Asunto(s)
Proteínas de Unión al ADN/agonistas , Compuestos Heterocíclicos con 2 Anillos/química , Quinolinas/química , Receptores Citoplasmáticos y Nucleares/agonistas , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Línea Celular , Simulación por Computador , Proteínas de Unión al ADN/metabolismo , Descubrimiento de Drogas , Humanos , Receptores X del Hígado , Ratones , Receptores Nucleares Huérfanos , Quinolinas/síntesis química , Quinolinas/farmacología , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Relación Estructura-ActividadRESUMEN
A structure-based approach was used to optimize our new class of quinoline LXR modulators leading to phenyl acetic acid substituted quinolines 15 and 16. Both compounds displayed good binding affinity for LXRbeta and LXRalpha and were potent activators in LBD transactivation assays. The compounds also increased expression of ABCA1 and stimulated cholesterol efflux in THP-1 cells. Quinoline 16 showed good oral bioavailability and in vivo efficacy in a LDLr knockout mouse model for lesions.
Asunto(s)
Anticolesterolemiantes/síntesis química , Aterosclerosis/tratamiento farmacológico , Proteínas de Unión al ADN/agonistas , Fenilacetatos/síntesis química , Quinolinas/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/biosíntesis , Animales , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacología , Sitios de Unión , Disponibilidad Biológica , Línea Celular , Colesterol/metabolismo , Proteínas de Unión al ADN/genética , Estabilidad de Medicamentos , Femenino , Humanos , Técnicas In Vitro , Ligandos , Receptores X del Hígado , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Receptores Nucleares Huérfanos , Fenilacetatos/química , Fenilacetatos/farmacología , Estructura Terciaria de Proteína , Quinolinas/química , Quinolinas/farmacología , Receptores Citoplasmáticos y Nucleares/genética , Relación Estructura-Actividad , Activación TranscripcionalRESUMEN
New diphenolic azoles as highly selective estrogen receptor-beta agonists are reported. The more potent and selective analogues of these series have comparable binding affinities for ERbeta as the natural ligand 17beta-estradiol but are >100-fold selective over ERalpha. Our design strategy not only followed a traditional SAR approach but also was supported by X-ray structures of ERbeta cocrystallized with various ligands as well as molecular modeling studies. These strategies enabled us to take advantage of a single conservative residue substitution in the ligand-binding pocket, ERalpha Met(421) --> ERbeta Ile(373), to optimize ERbeta selectivity. The 7-position-substituted benzoxazoles (Table 5) were the most selective ligands of both azole series, with ERB-041 (117) being >200-fold selective for ERbeta. The majority of ERbeta selective agonists tested that were at least approximately 50-fold selective displayed a consistent in vivo profile: they were inactive in several models of classic estrogen action (uterotrophic, osteopenia, and vasomotor instability models) and yet were active in the HLA-B27 transgenic rat model of inflammatory bowel disease. These data suggest that ERbeta-selective agonists are devoid of classic estrogenic effects and may offer a novel therapy to treat certain inflammatory conditions.
Asunto(s)
Isoxazoles/síntesis química , Fenoles/síntesis química , Receptores de Estrógenos/agonistas , Antagonistas de Andrógenos/síntesis química , Antagonistas de Andrógenos/química , Antagonistas de Andrógenos/farmacología , Animales , Animales Modificados Genéticamente , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Sitios de Unión , Temperatura Corporal/efectos de los fármacos , Enfermedades Óseas Metabólicas/prevención & control , Línea Celular Tumoral , Cristalografía por Rayos X , Diseño de Fármacos , Receptor beta de Estrógeno , Femenino , Antígeno HLA-B27/genética , Humanos , Isoxazoles/química , Isoxazoles/farmacología , Masculino , Ratones , Modelos Moleculares , Tamaño de los Órganos/efectos de los fármacos , Fenoles/química , Fenoles/farmacología , Próstata/anatomía & histología , Próstata/efectos de los fármacos , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos/química , Relación Estructura-Actividad , Transcripción Genética/efectos de los fármacos , Útero/anatomía & histología , Útero/efectos de los fármacosRESUMEN
A series of 2-(4-hydroxy-phenyl)-benzofuran-5-ols with relatively lipophilic groups in the 7-position of the benzofuran was prepared and the affinity and selectivity for ER beta was measured. Many of the analogues were found to be potent and selective ER beta ligands. Additional modifications at the benzofuran 4-position as well as at the 3'-position of the 2-phenyl group were found to further increase selectivity. Such modifications led to compounds with <10 nM potency and >100-fold selectivity for ER beta.
Asunto(s)
Benzofuranos/síntesis química , Receptor beta de Estrógeno/agonistas , Benzofuranos/metabolismo , Línea Celular Tumoral , Receptor beta de Estrógeno/química , Receptor beta de Estrógeno/metabolismo , Humanos , Proteína 4 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Ligandos , ARN Mensajero/análisis , Relación Estructura-ActividadRESUMEN
A new series of ERbeta (ERbeta) selective ligands has been prepared. One of the compounds 6, structurally related to the phytoestrogen apigenin 4, displays a binding preference for ERbeta over ERalpha of over 40-fold. In addition to its binding selectivity, 6 was able to potently induce metallothionein (an ERbeta specific response in human SAOS-2 cells) while demonstrating low potency in an ERalpha dependant ERE-tk luciferase assay in MCF-7 cells. Such receptor and cell selectivity could make 6 a useful molecular probe for better understanding the role of ERbeta in mammalian physiology.