RESUMEN
Estradiol receptors (ER), ERalpha and ERbeta, are ligand-dependent transcription factors that regulate gene expression. Human and murine genetics suggest that ERalpha is the key target for estradiol action on bone, uterus and breast. To date, the molecular mode of action of estradiol and selective estradiol receptor modulators (SERMs) on bone is not fully understood. This is exemplified by a lack of in vitro assays that reliably predict SERM agonist activities in vivo. We hypothesized that ligand-dependent ERalpha transrepression, via protein-protein interactions at AP1, may predict estrogenic effects on bone. We modeled this using the MMP1 promoter, which encodes an AP1 binding site. We show that ICI-182780, raloxifene, 4-hydroxytamoxifen and estradiol all exhibit differential agonistic activities on the MMP1 promoter by suppressing activity by 20-80%. Transrepression efficacy and potency correlated with both uterotrophic (R(2)=0.98) and osteoprotective (R(2)=0.80) potential in the ovariectomized rat. This identifies MMP1 promoter transrepression as an agonist activity commonly shared by AF2 agonists and "antagonists" alike. Mutation analysis showed that the repression by estradiol and SERMs required correct amino acid sequences in the AF-2 domain. For instance, L540Q AF2 mutation did not alter responses to raloxifene, although it greatly increased responses to ICI-182780 (threefold) and reduced estradiol's effect by 20%. Furthermore, all tested ligands repressed the MMP1 promoter through the L540Q mutant with identical efficacy. Together, these data suggest that estradiol and SERMs share common agonist transcriptional activity via protein-protein interactions at AP1.
Asunto(s)
Huesos/efectos de los fármacos , Receptor alfa de Estrógeno/agonistas , Metaloproteinasa 1 de la Matriz/genética , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Útero/efectos de los fármacos , Secuencias de Aminoácidos/fisiología , Animales , Huesos/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Estradiol/farmacología , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/fisiología , Femenino , Humanos , Metaloproteinasa 1 de la Matriz/metabolismo , Proteínas Mutantes/fisiología , Regiones Promotoras Genéticas/efectos de los fármacos , Estructura Terciaria de Proteína/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Células Tumorales Cultivadas , Útero/metabolismoRESUMEN
Estrogen receptor alpha (ERalpha) serine 118 (Ser118) phosphorylation modulates activation function-1 (AF1) function. Correct positioning of helix 12 promotes agonist-dependent recruitment of cyclin-dependent kinase-7 to catalyze this event. In this study we show robust cyclin-dependent kinase-7-independent, AF2 antagonist-induced Ser118 phosphorylation. Estradiol (E2) and ICI-182,780 (ICI-780) induce Ser118 phosphorylation of wild-type ERalpha and either of two helix 12 mutants, suggesting AF2-independent action, probably via shedding of 90-kDa heat shock protein. With E2 treatment, the predominantly nuclear, phosphorylated ERalpha in COS-1 cells is detergent soluble. Although levels of ICI-780-induced phosphorylation are profound, Ser118-phosphorylated ERalpha is aggregated over the nucleus or in the cytoplasm, fractionating with the cell debris and making detection in cleared lysates improbable. Selective ER modulators (SERMs) elicit a mixed response with phosphorylated ERalpha in both detergent-soluble and -insoluble compartments. Apparent ligand-induced loss of ERalpha protein from cleared lysates is thus due to ligand-induced redistribution into the pellet, not degradation. The COS-1 response to ICI-780 can be mimicked in MCF-7 cells treated with a proteasome inhibitor to block authentic ligand-induced degradation. With SERMs and antagonists, the magnitude of Ser118-phosphorylated receptor redistribution into the insoluble fraction of COS-1 cells correlates with the magnitude of authentic ERalpha degradation in MCF-7 cells. A strong inverse correlation with ligand-induced uterotropism in vivo (P < 0.0001) and direct correlation with AF2-independent transrepression of the matrix metalloprotease-1 promoter in endometrial cells in vitro are seen. These data suggest that ligand-induced Ser118 phosphorylation of ERalpha can be AF2 independent. Furthermore, they identify translocation of Ser118-phosphorylated ERalpha out of the nucleus, leading to cytoplasmic aggregation, as an antagonist pathway that may precede receptor degradation.
Asunto(s)
Antagonistas de Estrógenos/farmacología , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/metabolismo , Animales , Benzoquinonas , Células COS , Chlorocebus aethiops , Quinasas Ciclina-Dependientes/efectos de los fármacos , Quinasas Ciclina-Dependientes/metabolismo , Citoplasma/efectos de los fármacos , Citoplasma/metabolismo , Endometrio/citología , Endometrio/efectos de los fármacos , Estradiol/análogos & derivados , Estradiol/farmacología , Receptor alfa de Estrógeno/agonistas , Femenino , Fulvestrant , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/efectos de los fármacos , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Lactamas Macrocíclicas , Metaloproteinasa 1 de la Matriz/efectos de los fármacos , Metaloproteinasa 1 de la Matriz/genética , Tamaño de los Órganos/efectos de los fármacos , Fosforilación , Regiones Promotoras Genéticas , Quinonas/farmacología , Ratas , Ratas Sprague-Dawley , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Serina/metabolismo , Útero/efectos de los fármacos , Quinasa Activadora de Quinasas Ciclina-DependientesRESUMEN
Somatostatin inhibits both glucagon and insulin secretion. Glucagon significantly contributes to hyperglycemia in type 2 diabetes. Despite its function in the inhibition of glucagon secretion, somatostatin fails to reduce hyperglycemia in type 2 diabetes, due to a parallel suppression of insulin secretion. Five pharmacologically distinct somatostatin receptor subtypes (sst(1)-sst(5)) mediate the effects of somatostatin on a cellular level. Pancreatic A cells express sst(2), whereas B cells express sst(5). In this study, we describe a novel approach to the treatment of type 2 diabetes using a highly sst(2)-selective, nonpeptide agonist (compound 1). Compound 1 effectively inhibited glucagon secretion from pancreatic islets isolated from wild-type mice, whereas glucagon secretion from sst(2)-deficient islets was not suppressed. Compound 1 did not influence nonfasted insulin concentration. In sst(2)-deficient mice, compound 1 did not have any effects on glucagon or glucose levels, confirming its sst(2) selectivity. In animal models of type 2 diabetes in the nonfasted state, circulating glucagon and glucose levels were decreased after treatment with compound 1. In the fasting state, compound 1 lowered blood glucose by approximately 25%. In summary, small-molecule sst(2)-selective agonists that suppress glucagon secretion offer a novel approach toward the development of orally bioavailable drugs for treatment of type 2 diabetes.
Asunto(s)
Hipoglucemiantes/farmacología , Receptores de Somatostatina/agonistas , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Perros , Glucagón/metabolismo , Hormona del Crecimiento/metabolismo , Técnicas In Vitro , Insulina/metabolismo , Insulina/farmacología , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Ratas , Receptores de Somatostatina/genéticaRESUMEN
[reaction: see text] The synthesis of four bioactive analogues of the somatostatin (SRIF-14) mimetic, beta-d-glucoside (+)-2, in which the C1 indole side chain is replaced with indole surrogates, has been achieved. These congeners, possessing the naphthyl, benzothiophene, benzyl, and benzofuran substituents, were predicted to satisfy the electrostatic requirements of the tryptophan binding pocket of SRIF. Unlike the previously described C4 picolyl and pyrazinyl congeners, these ligands bind the hSST4 receptor.
Asunto(s)
Glucósidos/química , Glucósidos/síntesis química , Somatostatina/química , Sitios de Unión , Conformación Molecular , Imitación Molecular , Estructura Molecular , Electricidad Estática , Estereoisomerismo , Triptófano/químicaRESUMEN
In our continuing program exploring glucose-based peptidomimetics of somatostatin (SRIF-14), we sought to improve the water solubility of our glycosides. This led to insights into the nature of the ligand binding sites at the SRIF receptor. Replacement of the C4 benzyl substituent in glucoside (+)-2 with pyridinylmethyl or pyrazin-2-ylmethyl congeners increased water solubility and enhanced affinity for the human SRIF subtype receptor 4 (sst4). We attribute this effect to hydrogen bond formation. The pyridin-3-ylmethyl substituent at C4, when combined with the imidazol-4-ylmethyl group at C2, generated (-)-19, which has the highest affinity of a glucose-based peptidomimetic at a human SRIF receptor to date (K(i) 53 +/- 23 nM, n = 6 at sst4). The C4 heterocyclic congeners of glucosides bearing a 1-methoxy substituent rather than an indole side chain at the anomeric carbon, such as (+)-16, also provided information about the Trp(8) binding pocket. We correlated the SARs at both the C4 and the Trp(8) binding pockets with calculations of the electrostatic potentials of the diverse C4 aromatic substituents using Spartan 3-21G(*) MO analysis. These calculations provide an approximate analysis of a molecule's ability to interact within a receptor binding site. Our binding studies show that benzene and indole rings, but not pyridinylmethyl nor pyrazin-2-ylmethyl rings, can bind the hydrophobic Trp(8) binding pocket of sst4. The Spartan 3-21G(*) MO analysis reveals significant negative electrostatic potential in the region of the pi-clouds for the benzene and indole rings but not for the pyridinylmethyl or pyrazin-2-ylmethyl congeners. Our data further demonstrate that the replacement of benzene or indole side chains by heterocyclic aromatic rings typified by pyridine and pyrazine not only enhances water solubility and hydrogen bonding capacity as expected, but can also profoundly diminish the ability of the pi-cloud of the aromatic substituent to interact with side chains of an aromatic binding pocket such as that for Trp(8) of SRIF-14. Conversely, these calculations accommodate the experimental findings that pyrazin-2-ylmethyl and pyridinylmethyl substituents at C4- of C1-indole-substituted glycosides afford higher affinities at sst4 than the C4-benzyl group of (+)-2. This result is consistent with the high electron density in the plane of the heterocycle depicted in Figure 6 which can accept hydrogen bonds from the C4 binding pocket of the receptor. Unexpectedly, we found that the 2-fluoropyridin-5-ylmethyl analogue (+)-14 more closely resembles the binding affinity of (+)-8 than that of (+)-2, thus suggesting that (+)-14 represents a rare example of a carbon linked fluorine atom acting as a hydrogen bond acceptor. We attribute this result to the ability of the proton to bind the nitrogen and fluorine atoms simultaneously in a bifurcated arrangement. At the NK1 receptor of substance P (SP), the free hydroxyl at C4 optimizes affinity.
Asunto(s)
Glicósidos/química , Imidazoles/química , Pirazinas/química , Piridinas/química , Receptores de Somatostatina/química , Sitios de Unión , Humanos , Enlace de Hidrógeno , Hidrólisis , Imidazoles/síntesis química , Ligandos , Proteínas de la Membrana , Modelos Moleculares , Imitación Molecular , Péptidos/química , Pirazinas/síntesis química , Piridinas/síntesis química , Teoría Cuántica , Ensayo de Unión Radioligante , Receptores de Neuroquinina-1/química , Solubilidad , Electricidad Estática , Relación Estructura-ActividadRESUMEN
The discovery and synthesis of dihydrobenzoxathiins as potent, ERalpha subtype selective ligands are described. The most active analogue, 4-D, was found to be 50-fold selective in a competitive binding assay and 100-fold selective in a transactivation assay in HEK-293 cells. The alpha selectivity was postulated to lie in the interaction of the sulfur atom of the benzoxathiin ring with the two discriminating residues in the binding pocket of the receptor isoforms.
Asunto(s)
Oxatiinas/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Animales , Sitios de Unión , Unión Competitiva , Línea Celular , Cristalografía por Rayos X , Receptor alfa de Estrógeno , Receptor beta de Estrógeno , Femenino , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Tamaño de los Órganos/efectos de los fármacos , Oxatiinas/química , Oxatiinas/farmacología , Receptores de Estrógenos/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Activación Transcripcional , Útero/efectos de los fármacosRESUMEN
Estrogen action is mediated via two estrogen receptor (ER) subtypes, ERalpha and ERbeta. Selective ER modulators with balanced high affinity for ERalpha and ERbeta have been developed as therapeutics for the treatment of a variety of diseases, including hormone-responsive breast cancer and osteoporosis. Recent data based primarily on the evaluation of ER-knockout mice have revealed that ERalpha and ERbeta may regulate separate and distinct biological processes. The identification of ERbeta specific ligands could further enhance our understanding of ERbeta biology. In addition, compounds targeting ERbeta may prove useful as therapeutic agents with activity profiles distinguishable from that of estradiol. To discover novel selective ligands for ERbeta, we developed and characterized a cell-based Gal4-ERbeta beta-lactamase reporter gene assay (GERTA) in CHO cells for the ligand-induced activation of the human ERbeta. The sensitivity and selectivity of this assay were found to be comparable to those of an ER ligand-binding assay. The assay was optimized for screening in an ultra high throughput 3456-well nanoplate format and was successfully used to screen a large compound collection for ERbeta agonists. Compounds identified in a primary screen were tested in an in vitro ligand-binding assay to characterize further the selectivity and potency for ERbeta.
Asunto(s)
Nanotecnología/métodos , Receptores de Estrógenos/agonistas , Receptores de Estrógenos/metabolismo , Factores de Transcripción/metabolismo , Activación Transcripcional/fisiología , beta-Lactamasas/metabolismo , Animales , Células CHO , Cricetinae , Relación Dosis-Respuesta a Droga , Estradiol/metabolismo , Estradiol/farmacología , Receptor beta de Estrógeno , Vectores Genéticos , Humanos , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Receptores de Estrógenos/genética , Factores de Transcripción/genética , beta-Lactamasas/genéticaRESUMEN
OBJECTIVE: To test the role of ERbeta in the control of estrogen-dependent thermoregulation in rats. METHODS: Test the ability of an ERbeta-selective ligand to suppress the elevation in basal rat tail skin temperature (TST) caused by ovariectomy (OVX). RESULTS: ERbeta-19 is a tetrahydrofluorenone ERbeta-selective ligand that displaces 0.1 nM estradiol from ERbeta with an IC50 of 1.8 nM compared to an IC50 of 141 nM for ERalpha. Like estradiol, it acts as an agonist on ERbeta-mediated transactivation and transrepression with 25- and 60-fold selectivity, respectively, over ERalpha-controlled transcription. Administration of estradiol to estrogen-depleted rats suppresses the ovariectomy-induced elevation of TST. Similar treatment of OVX rats with ERbeta-19 also results in suppression of elevated TST. However, in contrast to estradiol, ERbeta-19 does not suppress body weight, does not increase uterine weight, nor does it stimulate uterocalin biomarker expression which is under the control of ERalpha. Thus, the ERbeta-19 suppression of rat TST is mediated by ERbeta without eliciting the activity of ERalpha. CONCLUSION: Estrogen-sensitive thermoregulation in ovariectomized rats can be controlled by an ERbeta-selective ligand.
Asunto(s)
Regulación de la Temperatura Corporal/genética , Estradiol/farmacología , Receptor beta de Estrógeno/agonistas , Fluorenos/farmacología , Temperatura Cutánea/genética , Animales , Regulación de la Temperatura Corporal/fisiología , Peso Corporal/efectos de los fármacos , Estradiol/genética , Estradiol/metabolismo , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Femenino , Regulación de la Expresión Génica , Ligandos , Lipocalinas/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Ovariectomía , Ratas , Ratas Sprague-Dawley , Temperatura Cutánea/fisiología , Cola (estructura animal) , Útero/metabolismoRESUMEN
A series of androstene-3,5-diene derivatives were prepared. Despite lacking the C-3 hydroxyl previously believed necessary for ER activity, some of the analogs retained surprising affinity for ER-beta. For example, diene 4 retained excellent selectivity and potency as an ER-beta agonist and was more selective for ER-beta over the androgen receptor (AR).
Asunto(s)
Androstadienos/síntesis química , Androstadienos/farmacología , Receptor beta de Estrógeno/agonistas , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Androstadienos/química , Animales , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Ratas , Receptores Androgénicos/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/químicaRESUMEN
A novel class of indole ligands for estrogen receptor alpha have been discovered which exhibit potent affinity and high selectivity. Substitution of the bazedoxifene skeleton to the linker present in the HTS lead 1a provided 22b which was found to be 130-fold alpha-selective and acted as an antagonist of estradiol activity in uterine tissue and MCF-7 cancer cells.
Asunto(s)
Receptor alfa de Estrógeno/antagonistas & inhibidores , Indoles/química , Indoles/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Antagonistas de Estrógenos/química , Antagonistas de Estrógenos/farmacología , Femenino , Humanos , Concentración 50 Inhibidora , Ligandos , Útero/efectos de los fármacosRESUMEN
A series of bridged androstenediol derivatives was prepared. The bridged compounds exhibited reduced ER-beta selectivity relative to uncyclized analogs.
Asunto(s)
Androstenodioles/síntesis química , Receptor beta de Estrógeno/antagonistas & inhibidores , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Androstenodioles/farmacología , Ciclización , Receptor beta de Estrógeno/química , Receptor beta de Estrógeno/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of 6H-benzo[c]chromen-6-one and 6H-benzo[c]chromene derivatives were prepared, and the affinity and selectivity for ERalpha and ERbeta was measured. Many of the analogs were found to be potent and selective ERbeta agonists. Bis hydroxyl at positions 3 and 8 is essential for activity in a HTRF coactivator recruitment assay. Additional modifications at both phenyl rings led to compounds with ERbeta<10nM potency and >100-fold selectivity over ERalpha.
Asunto(s)
Derivados del Benceno/síntesis química , Benzopiranos/síntesis química , Receptor beta de Estrógeno/agonistas , Derivados del Benceno/química , Derivados del Benceno/metabolismo , Benzopiranos/química , Benzopiranos/metabolismo , Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Fluoroinmunoensayo , Humanos , Ligandos , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A series of 2-9a bridged tetrahydrofluorenone derivatives were prepared which exhibited significant binding affinity for ERbeta and were highly selective.
Asunto(s)
Receptor beta de Estrógeno/química , Receptor beta de Estrógeno/metabolismo , Fluorenos/química , Hidrógeno/química , Fluorenos/síntesis química , Humanos , Ligandos , Espectroscopía de Resonancia Magnética , Conformación MolecularRESUMEN
Several tetrahydrofluorenones with a triazole fused across C7-C8 showed high levels of ERbeta-selectivity and were found to be potent ERbeta-agonists. As a class they demonstrate improved oral bioavailability in the rat over a parent class of 7-hydroxy-tetrahydrofluorenones. The most selective agonist displayed 5.7 nM affinity and 333-fold selectivity for ERbeta.
Asunto(s)
Compuestos Azo/síntesis química , Compuestos Azo/farmacología , Receptor beta de Estrógeno/agonistas , Fluorenos/química , Fluorenos/farmacología , Animales , Compuestos Azo/química , Compuestos Azo/farmacocinética , Receptor beta de Estrógeno/metabolismo , Fluorenos/síntesis química , Fluorenos/farmacocinética , Humanos , Ligandos , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
A series of 19-substituted androstenediol derivatives was prepared. Some of the novel analogs were surprisingly potent and selective ligands for ER-beta.
Asunto(s)
Androstenodiol/análogos & derivados , Androstenodiol/farmacología , Receptor beta de Estrógeno/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Androstenodiol/síntesis química , Cristalografía por Rayos X , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The ring oxygen and sulfur analogs of lasofoxifene, 1a and 1b, were synthesized in an attempt to impart ERalpha selectivity, as found in the closely related dihydrobenzoxathiin compound I, recently discovered in these laboratories. The resulting isochroman and isothiochroman compounds were found to exhibit equipotent binding affinities to the ER isoforms and were less active in the inhibition of estradiol-triggered uterine growth when compared to I and lasofoxifene.
Asunto(s)
Cromanos/síntesis química , Cromanos/farmacología , Receptor alfa de Estrógeno/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Estradiol/farmacología , Femenino , Humanos , Concentración 50 Inhibidora , Ligandos , Modelos Moleculares , Unión Proteica , Isoformas de Proteínas , Relación Estructura-Actividad , Útero/efectos de los fármacos , Útero/crecimiento & desarrolloRESUMEN
Two novel side chains which had previously been found to enhance antagonist activity in the dihydrobenzoxathiin SERM series were applied to three existing platforms. The novel side chains did not improve the antagonist activity of the existing platforms.
Asunto(s)
Receptor alfa de Estrógeno/antagonistas & inhibidores , Oxatiinas/química , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Animales , Ligandos , RatasRESUMEN
An optimized side chain for dihydrobenzoxathiin SERAMs was discovered and attached to four dihydrobenzoxathiin platforms. The novel SERAMs show exceptional estrogen antagonist activity in uterine tissue and an MCF-7 breast cancer cell assay.
Asunto(s)
Oxatiinas/síntesis química , Receptores de Estrógenos/química , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Antagonistas de Estrógenos/síntesis química , Antagonistas de Estrógenos/farmacología , Femenino , Humanos , Oxatiinas/farmacología , Ratas , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Relación Estructura-Actividad , Útero/efectos de los fármacos , Útero/crecimiento & desarrolloRESUMEN
A series of dihydrobenzoxathiin SERAMs with alkylated pyrrolidine side chains or alkylated linkers was prepared. Minor modifications in the side chain or linker resulted in significant effects on biological activity, especially in uterine tissue.
Asunto(s)
Oxatiinas/farmacología , Pirrolidinas/química , Receptores de Estrógenos/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Ligandos , Modelos Moleculares , Oxatiinas/química , Receptores de Estrógenos/metabolismoRESUMEN
The discovery, synthesis, and SAR of chromanes as ER alpha subtype selective ligands are described. X-ray studies revealed that the origin of the ER alpha-selectivity resulted from a C-4 trans methyl substitution to the cis-2,3-diphenyl-chromane platform. Selected compounds from this class demonstrated very potent in vivo antagonism of estradiol in an immature rat uterine weight assay, effectively inhibited ovariectomy-induced bone resorption in a 42 days treatment paradigm, and lowered serum cholesterol levels in ovx'd adult rat models. The best antagonists 8F and 12F also exhibited potent inhibition of MCF-7 cell growth and were shown to be estrogen receptor down-regulators (SERDs).