RESUMEN
Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a CGG STR represses FMR1 via local DNA methylation. Here, we find megabase-scale H3K9me3 domains on autosomes and encompassing FMR1 on the X chromosome in FXS patient-derived iPSCs, iPSC-derived neural progenitors, EBV-transformed lymphoblasts, and brain tissue with mutation-length CGG expansion. H3K9me3 domains connect via inter-chromosomal interactions and demarcate severe misfolding of TADs and loops. They harbor long synaptic genes replicating at the end of S phase, replication-stress-induced double-strand breaks, and STRs prone to stepwise somatic instability. CRISPR engineering of the mutation-length CGG to premutation length reverses H3K9me3 on the X chromosome and multiple autosomes, refolds TADs, and restores gene expression. H3K9me3 domains can also arise in normal-length iPSCs created with perturbations linked to genome instability, suggesting their relevance beyond FXS. Our results reveal Mb-scale heterochromatinization and trans interactions among loci susceptible to instability.
Asunto(s)
Síndrome del Cromosoma X Frágil , Humanos , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/metabolismo , Expansión de Repetición de Trinucleótido , Metilación de ADN , Mutación , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismoRESUMEN
The identification of activating mutations in NOTCH1 in 50% of T cell acute lymphoblastic leukemia has generated interest in elucidating how these mutations contribute to oncogenic transformation and in targeting the pathway. A phenotypic screen identified compounds that interfere with trafficking of Notch and induce apoptosis via an endoplasmic reticulum (ER) stress mechanism. Target identification approaches revealed a role for SLC39A7 (ZIP7), a zinc transport family member, in governing Notch trafficking and signaling. Generation and sequencing of a compound-resistant cell line identified a V430E mutation in ZIP7 that confers transferable resistance to the compound NVS-ZP7-4. NVS-ZP7-4 altered zinc in the ER, and an analog of the compound photoaffinity labeled ZIP7 in cells, suggesting a direct interaction between the compound and ZIP7. NVS-ZP7-4 is the first reported chemical tool to probe the impact of modulating ER zinc levels and investigate ZIP7 as a novel druggable node in the Notch pathway.
Asunto(s)
Proteínas de Transporte de Catión/genética , Estrés del Retículo Endoplásmico/fisiología , Receptor Notch1/genética , Animales , Apoptosis , Proteínas Portadoras/metabolismo , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/fisiología , Línea Celular , Transformación Celular Neoplásica , Retículo Endoplásmico/fisiología , Humanos , Mutación , Transporte de Proteínas , Receptor Notch1/fisiología , Transducción de Señal , Zinc/metabolismoRESUMEN
Fragile X syndrome (FXS) is the most common genetic form of intellectual disability caused by a CGG repeat expansion in the 5'-UTR of the Fragile X mental retardation gene FMR1, triggering epigenetic silencing and the subsequent absence of the protein, FMRP. Reactivation of FMR1 represents an attractive therapeutic strategy targeting the genetic root cause of FXS. However, largely missing in the FXS field is an understanding of how much FMR1 reactivation is required to rescue FMRP-dependent mutant phenotypes. Here, we utilize FXS patient-derived excitatory neurons to model FXS in vitro and confirm that the absence of FMRP leads to neuronal hyperactivity. We further determined the levels of FMRP and the percentage of FMRP-positive cells necessary to correct this phenotype utilizing a mixed and mosaic neuronal culture system and a combination of CRISPR, antisense and expression technologies to titrate FMRP in FXS and WT neurons. Our data demonstrate that restoration of greater than 5% of overall FMRP expression levels or greater than 20% FMRP-expressing neurons in a mosaic pattern is sufficient to normalize a FMRP-dependent, hyperactive phenotype in FXS iPSC-derived neurons.
Asunto(s)
Síndrome del Cromosoma X Frágil , Células Madre Pluripotentes Inducidas , Epigénesis Genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Neuronas/metabolismoRESUMEN
Facioscapulohumeral muscular dystrophy (FSHD) is caused by the loss of repression at the D4Z4 locus leading to aberrant double homeobox 4 (DUX4) expression in skeletal muscle. Activation of this early embryonic transcription factor results in the expression of its target genes causing muscle fiber death. Although progress toward understanding the signals driving DUX4 expression has been made, the factors and pathways involved in the transcriptional activation of this gene remain largely unknown. Here, we describe the identification and characterization of p38α as a novel regulator of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent, and specific inhibitors of p38α/ß, we show a robust reduction of DUX4 expression, activity, and cell death across patient-derived FSHD1 and FSHD2 lines. RNA-seq profiling reveals that a small number of genes are differentially expressed upon p38α/ß inhibition, the vast majority of which are DUX4 target genes. Our results reveal a novel and apparently critical role for p38α in the aberrant activation of DUX4 in FSHD and support the potential of p38α/ß inhibitors as effective therapeutics to treat FSHD at its root cause. SIGNIFICANCE STATEMENT: Using patient-derived facioscapulohumeral muscular dystrophy (FSHD) myotubes, we characterize the pharmacological relationships between p38α/ß inhibition, double homeobox 4 (DUX4) expression, its downstream transcriptional program, and muscle cell death. p38α/ß inhibition results in potent and specific DUX4 downregulation across multiple genotypes without significant effects in the process of myogenesis in vitro. These findings highlight the potential of p38α/ß inhibitors for the treatment of FSHD, a condition that today has no approved therapies.
Asunto(s)
Proteínas de Homeodominio/metabolismo , Distrofia Muscular Facioescapulohumeral/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Muerte Celular/fisiología , Línea Celular , Regulación de la Expresión Génica/fisiología , Humanos , Células Musculares/metabolismo , Músculo Esquelético/metabolismoRESUMEN
Indole- and azaindole-based glyoxylyl amide derivatives have been described as HIV-1 attachment inhibitors (AIs) that act by blocking the interaction between the viral gp120 coat protein and the human host cell CD4 receptor. As part of an effort to more deeply understand the role of the indole/azaindole heterocycle in the expression of antiviral activity, a survey of potential replacements was conducted using parallel synthesis methodology. The design and optimization was guided by a simple 2-dimensional overlay based on an overall planar topography between the indole/azaindole and C-7 substituents that had been deduced from structure-activity studies leading to the discovery of temsavir (3). 2-Substituted naphthalene- and quinoline-derived chemotypes emerged as the most interesting prototypes, with C-5 and C-6 substituents enhancing antiviral potency. Despite the fact that neither of these chemotypes incorporated a H-bond donor that has been shown to engage the side chain carboxylate of Asp113 in gp120, the antiviral potency of several analogues met or exceeded that of 3, demonstrating that engaging Asp113 is not a prerequisite for potent antiviral activity.
Asunto(s)
Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Indoles/farmacología , Acoplamiento Viral/efectos de los fármacos , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Humanos , Indoles/síntesis química , Indoles/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
BACKGROUND: Fragile X syndrome (FXS) is characterized by physical abnormalities, anxiety, intellectual disability, hyperactivity, autistic behaviors, and seizures. Abnormal neuronal development in FXS is poorly understood. Data on patients with FXS remain scarce, and FXS animal models have failed to yield successful therapies. In vitro models do not fully recapitulate the morphology and function of human neurons. METHODS: To mimic human neuron development in vivo, we coinjected neural precursor cells derived from FXS patient-derived induced pluripotent stem cells and neural precursor cells derived from corrected isogenic control induced pluripotent stem cells into the brain of neonatal immune-deprived mice. RESULTS: The transplanted cells populated the brain and a proportion differentiated into neurons and glial cells. Immunofluorescence and single and bulk RNA sequencing analyses showed accelerated maturation of FXS neurons after an initial delay. Additionally, we found increased percentages of Arc- and Egr-1-positive FXS neurons and wider dendritic protrusions of mature FXS striatal medium spiny neurons. CONCLUSIONS: This transplantation approach provides new insights into the alterations of neuronal development in FXS by facilitating physiological development of cells in a 3-dimensional context.
Asunto(s)
Síndrome del Cromosoma X Frágil , Células-Madre Neurales , Humanos , Ratones , Animales , Síndrome del Cromosoma X Frágil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Fenotipo , Encéfalo/metabolismo , Ratones NoqueadosRESUMEN
1-(4-Benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1a) has been characterized as an inhibitor of HIV-1 attachment that interferes with the interaction of viral gp120 with the host cell receptor CD4. In previous studies, the effect of indole substitution pattern on antiviral activity was probed. In this Letter, the effect of structural variation of the benzamide moiety is described, a study that reveals the potential or the phenyl moiety to be replaced by five-membered heterocyclic rings and a restricted tolerance for the introduction of substituents to the phenyl ring.
Asunto(s)
Fármacos Anti-VIH/química , Benzamidas/química , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Inhibidores de Fusión de VIH/química , Indoles/química , Piperazinas/química , Acoplamiento Viral/efectos de los fármacos , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Línea Celular , Proteína gp120 de Envoltorio del VIH/metabolismo , Inhibidores de Fusión de VIH/síntesis química , Inhibidores de Fusión de VIH/farmacología , Humanos , Indoles/síntesis química , Indoles/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Relación Estructura-ActividadRESUMEN
The effects of introducing simple halogen, alkyl, and alkoxy substituents to the 4, 5, 6 and 7 positions of 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione, an inhibitor of the interaction between HIV gp120 and host cell CD4 receptors, on activity in an HIV entry assay was examined. Small substituents at C-4 generally resulted in increased potency whilst substitution at C-7 was readily tolerated and uniformly produced more potent HIV entry inhibitors. Substituents deployed at C-6 and, particularly, C-5 generally produced a modest to marked weakening of potency compared to the prototype. Small alkyl substituents at N-1 exerted minimal effect on activity whilst increasing the size of the alkyl moiety led to progressively reduced inhibitory properties. These studies establish a basic understanding of the indole element of the HIV attachment inhibitor pharmacophore.
Asunto(s)
Inhibidores de Fusión de VIH/química , Inhibidores de Fusión de VIH/farmacología , VIH-1/efectos de los fármacos , Indoles/farmacología , Acoplamiento Viral/efectos de los fármacos , Animales , Línea Celular , Perros , Proteína gp120 de Envoltorio del VIH/metabolismo , Infecciones por VIH/prevención & control , Humanos , Indoles/química , Indoles/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
A selective estrogen receptor modulator (SERM) for the potential treatment of hot flushes is described. (R)-(+)-7,9-difluoro-5-[4-(2-piperidin-1-ylethoxy)phenyl]-5H-6-oxachrysen-2-ol, LSN2120310, potently binds ERalpha and ERbeta and is an antagonist in MCF-7 breast adenocarcinoma and Ishikawa uterine cancer cell lines. The compound is a potent estrogen antagonist in the rat uterus. In ovariectomized rats, the compound lowers cholesterol, maintains bone mineral density, and is efficacious in a morphine dependent rat model of hot flush efficacy.
Asunto(s)
Benzopiranos/síntesis química , Antagonistas de Estrógenos/síntesis química , Sofocos/tratamiento farmacológico , Naftalenos/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Adenocarcinoma , Animales , Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacología , Benzopiranos/química , Benzopiranos/farmacología , Densidad Ósea/efectos de los fármacos , Neoplasias de la Mama , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colesterol/sangre , Antagonistas de Estrógenos/química , Antagonistas de Estrógenos/farmacología , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Femenino , Humanos , Morfina/farmacología , Naftalenos/química , Naftalenos/farmacología , Ovariectomía , Ratas , Ratas Sprague-Dawley , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Estereoisomerismo , Neoplasias Uterinas , Útero/efectos de los fármacos , Útero/crecimiento & desarrolloRESUMEN
The use of selective estrogen receptor modulators for the treatment of estrogen-dependent diseases in premenopausal women has been hindered by undesirable ovarian stimulation and associated risks of ovarian cysts. We have identified a selective estrogen receptor modulator compound (LY2066948) that is a strong estrogen antagonist in the uterus yet has minimal effects on the ovaries of rats. LY2066948 binds with high affinity to both estrogen receptors and has potent estrogen antagonist activity in human uterine and breast cancer cells. Oral administration of LY2066948 to immature rats blocked uterine weight gain induced by ethynyl estradiol with an ED50 of 0.07 mg/kg. Studies in mature rats demonstrated that LY2066948 decreases uterine weight by 51% after 35 d treatment, confirming potent uterine antagonist activity over several estrous cycles. This strong uterine response contrasted with the minimal effects on the ovaries: serum estradiol levels remained within the normal range, whereas histologic evaluation showed granulosa cell hyperplasia in few of the rats. Bone studies demonstrated that LY2066948 prevented ovariectomy-induced bone loss and treatment of ovary-intact rats caused no bone loss, confirming estrogen receptor agonist skeletal effects. Collectively, these data show that LY2066948 exhibits a tissue-specific profile consistent with strong antagonist activity in the uterus, agonist activity in bone, and minimal effects in the ovaries.
Asunto(s)
Huesos/fisiología , Naftalenos/farmacología , Inducción de la Ovulación , Piperidinas/farmacología , Receptores de Estrógenos/fisiología , Útero/fisiología , Animales , Huesos/efectos de los fármacos , Línea Celular Tumoral , Etinilestradiol/farmacología , Femenino , Humanos , Cinética , Ovariectomía , Ratas , Receptores de Estrógenos/agonistas , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Estrógenos/efectos de los fármacos , Maduración Sexual , Útero/efectos de los fármacosRESUMEN
The design of a novel selective estrogen receptor modulator (SERM) for the potential treatment of uterine leiomyoma is described. 16 (LY2066948-HCl) binds with high affinity to estrogen receptors alpha and beta (ERalpha and ERbeta, respectively) and is a potent uterine antagonist with minimal effects on the ovaries as determined by serum biomarkers and histologic evaluation.
Asunto(s)
Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor beta de Estrógeno/antagonistas & inhibidores , Leiomioma/tratamiento farmacológico , Naftalenos/síntesis química , Ovario/efectos de los fármacos , Piperidinas/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Neoplasias Uterinas/tratamiento farmacológico , Útero/efectos de los fármacos , Animales , Sitios de Unión , Disponibilidad Biológica , Línea Celular , Proliferación Celular , Estradiol/sangre , Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/química , Receptor beta de Estrógeno/agonistas , Femenino , Humanos , Glándulas Mamarias Animales/citología , Glándulas Mamarias Animales/efectos de los fármacos , Modelos Moleculares , Naftalenos/química , Naftalenos/farmacología , Tamaño de los Órganos/efectos de los fármacos , Ovario/anatomía & histología , Ovario/metabolismo , Piperidinas/química , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Relación Estructura-Actividad , Útero/anatomía & histología , Útero/citología , Útero/metabolismoRESUMEN
The pharmaceutical industry remains under huge pressure to address the high attrition rates in drug development. Attempts to reduce the number of efficacy- and safety-related failures by analysing possible links to the physicochemical properties of small-molecule drug candidates have been inconclusive because of the limited size of data sets from individual companies. Here, we describe the compilation and analysis of combined data on the attrition of drug candidates from AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer. The analysis reaffirms that control of physicochemical properties during compound optimization is beneficial in identifying compounds of candidate drug quality and indicates for the first time a link between the physicochemical properties of compounds and clinical failure due to safety issues. The results also suggest that further control of physicochemical properties is unlikely to have a significant effect on attrition rates and that additional work is required to address safety-related failures. Further cross-company collaborations will be crucial to future progress in this area.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Descubrimiento de Drogas/métodos , Industria Farmacéutica/métodos , Drogas en Investigación , Animales , Sistemas de Liberación de Medicamentos/estadística & datos numéricos , Sistemas de Liberación de Medicamentos/tendencias , Descubrimiento de Drogas/estadística & datos numéricos , Descubrimiento de Drogas/tendencias , Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/estadística & datos numéricos , Evaluación Preclínica de Medicamentos/tendencias , Industria Farmacéutica/estadística & datos numéricos , Industria Farmacéutica/tendencias , Drogas en Investigación/administración & dosificación , Humanos , Estadística como Asunto/métodos , Estadística como Asunto/tendenciasRESUMEN
The estrogen receptor is a regulator of a wide range of physiological functions, including the female reproductive system, in addition to bone, cardiovascular and CNS function. ER ligands have been approved for the treatment of menopausal symptoms, breast cancer and osteoporosis, however the search continues for new modulators of ER function with improved properties. Progress in medicinal chemistry programs has resulted in the identification of structurally diverse molecules with unique biological properties. Recent advances in the design and synthesis of these non-steroidal and steroidal estrogen receptor ligands is reviewed. The relationship between the structural features of the ligand and receptor function is also discussed.
Asunto(s)
Moduladores de los Receptores de Estrógeno/química , Receptores de Estrógenos/metabolismo , Animales , Unión Competitiva , Moduladores de los Receptores de Estrógeno/farmacología , Humanos , Ligandos , Estructura Molecular , Receptores de Estrógenos/fisiología , Relación Estructura-ActividadRESUMEN
Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.
Asunto(s)
Fármacos Anti-VIH/farmacología , Antígenos CD4/metabolismo , Proteína gp120 de Envoltorio del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/metabolismo , Indoles/farmacología , Piperazinas/farmacología , Administración Oral , Animales , Fármacos Anti-VIH/farmacocinética , Disponibilidad Biológica , Antagonistas de los Receptores CCR5 , Perros , Humanos , Indoles/química , Indoles/farmacocinética , Infusiones Intravenosas , Macaca fascicularis , Piperazinas/química , Piperazinas/farmacocinética , Ratas , Receptores CXCR4/antagonistas & inhibidoresRESUMEN
A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel synthesis strategies were employed to produce compounds with good in vitro and in vivo gamma-secretase activity.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Sulfonamidas/química , Sulfonamidas/farmacología , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ratones , Ratones Transgénicos , Estructura Molecular , Unión ProteicaRESUMEN
Structure-activity relationship studies are described, which led to the discovery of novel selective estrogen receptor modulators (SERMs) for the potential treatment of uterine fibroids. The SAR studies focused on limiting brain exposure and were guided by computational properties. Compounds with limited impact on the HPO axis were selected using serum estrogen levels as a biomarker for ovarian stimulation.
Asunto(s)
Leiomioma/tratamiento farmacológico , Ovario/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Animales , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Estrógenos/sangre , Femenino , Humanos , Modelos Químicos , Ovario/metabolismo , Ratas , Ratas Sprague-Dawley , Moduladores Selectivos de los Receptores de Estrógeno/química , Programas Informáticos , Relación Estructura-ActividadRESUMEN
A new series of estrogen receptor ligands based on a 6-hydroxy-tetrahydroquinoline scaffold is described, in addition to their binding affinity and functional activity in MCF-7 cells. Several 1,2-disubstituted tetrahydroquinolines bearing a basic side chain were shown to be high affinity ligands and antagonists in the MCF-7 proliferation assay. Compounds lacking the basic side chain were agonists in the MCF-7 assay.
Asunto(s)
Hidroxiquinolinas/química , Hidroxiquinolinas/farmacología , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , División Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Hidroxiquinolinas/síntesis química , Concentración 50 Inhibidora , Ligandos , Receptores de Estrógenos/agonistas , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Relación Estructura-ActividadRESUMEN
Inhibitors of amyloid-beta (Abeta) protein production have been widely pursued as a potential treatment for Alzheimer's disease. Following the identification of a 5 microM screening hit, SAR was initiated using solid-phase synthetic techniques. Two series of alpha-hydroxy esters and ketones which are sub-micromolar inhibitors of Abeta production were identified. The most potent alpha-hydroxyketone identified is approximately 30-fold more potent than the initial lead.
Asunto(s)
Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/biosíntesis , Ésteres/síntesis química , Ésteres/farmacología , Diseño de Fármacos , Ensayo de Inmunoadsorción Enzimática , Indicadores y Reactivos , Relación Estructura-ActividadRESUMEN
For selective estrogen receptor modulators (SERMs), the orientation of the basic side chain relative to the SERM core has a significant impact on function. The synthesis and biological evaluation of two series of SERMs are disclosed, where the ligand side chain is constrained to adopt a defined orientation. Compounds where the side chain is forced into the plane of the SERM core have a different profile compared to those compounds where the side chain is pseudo-orthogonal, particularly with regard to antagonism of estradiol action on an Ishikawa uterine cell line.
Asunto(s)
Naftalenos/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Tiofenos/síntesis química , Animales , Línea Celular , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Ligandos , Naftalenos/química , Naftalenos/farmacología , Ensayo de Unión Radioligante , Ratas , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacología , Útero/efectos de los fármacos , Útero/fisiologíaRESUMEN
Using a cell-based assay, we have identified optimal residues and key recognition elements necessary for inhibition of gamma-secretase. An (S)-hydroxy group or 3,5-difluorophenylacetyl group at the amino terminus and N-methyltertiary amide moiety at the carboxy terminus provided potent gamma-secretase inhibitors with an IC(50) <10 nM.