RESUMEN
In an effort to find new and safer treatments for osteoporosis and frailty, we describe a novel series of selective androgen receptor modulators (SARMs). Using a structure-based approach, we identified compound 7, a potent AR (ARE EC50 = 0.34 nM) and selective (N/C interaction EC50 = 1206 nM) modulator. In vivo data, an AR LBD X-ray structure of 7, and further insights from modeling studies of ligand receptor interactions are also presented.
Asunto(s)
Anabolizantes/química , Andrógenos/química , Nitrilos/química , Pirroles/química , Receptores Androgénicos/metabolismo , Anabolizantes/síntesis química , Anabolizantes/farmacocinética , Anabolizantes/farmacología , Andrógenos/síntesis química , Andrógenos/farmacocinética , Andrógenos/farmacología , Animales , Cristalografía por Rayos X , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Masculino , Simulación del Acoplamiento Molecular , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Nitrilos/síntesis química , Nitrilos/farmacología , Tamaño de los Órganos/efectos de los fármacos , Especificidad de Órganos , Próstata/efectos de los fármacos , Próstata/fisiología , Pirroles/síntesis química , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Vesículas Seminales/efectos de los fármacos , Vesículas Seminales/fisiología , Relación Estructura-ActividadRESUMEN
The discovery of novel intervention points in the inflammatory pathway has been a focus of drug development in recent years. We have identified pathway selective ligands for the estrogen receptor (ER) that inhibit NF-kappaB mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules and inflammatory enzymes. SAR development of a series of 4-(Indazol-3-yl)-phenols has led to the identification of WAY-169916 an orally active non-steroidal ligand with the potential use in the treatment of inflammatory diseases without the classical proliferative effects associated with non-selective estrogens.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Pirazoles/uso terapéutico , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Estrógenos/inmunología , Enfermedad Crónica , Humanos , Ligandos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Pathway-selective ligands for the estrogen receptor (ER) inhibit NF-kappaB-mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules, and inflammatory enzymes. SAR development of a series of 4-(indazol-3-yl)phenols has led to the identification of WAY-169916 an orally active nonsteroidal ligand with the potential use in the treatment of rheumatoid arthritis without the classical proliferative effects associated with estrogens.
Asunto(s)
Antiinflamatorios/síntesis química , Artritis Reumatoide/tratamiento farmacológico , Indazoles/síntesis química , Fenoles/síntesis química , Receptores de Estrógenos/efectos de los fármacos , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Línea Celular , Receptor alfa de Estrógeno/química , Receptor alfa de Estrógeno/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/química , Receptor beta de Estrógeno/efectos de los fármacos , Receptor beta de Estrógeno/metabolismo , Humanos , Indazoles/química , Indazoles/farmacología , Ligandos , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , FN-kappa B/biosíntesis , FN-kappa B/genética , Fenoles/química , Fenoles/farmacología , Ratas , Ratas Endogámicas Lew , Receptores de Estrógenos/química , Receptores de Estrógenos/metabolismo , Relación Estructura-ActividadRESUMEN
Androgenetic alopecia (AGA), commonly known as male pattern baldness, is a form of hair loss that occurs in both males and females. Although the exact cause of AGA is not known, it is associated with genetic predisposition through traits related to androgen synthesis/metabolism and androgen signaling mediated by the androgen receptor (AR). Current therapies for AGA show limited efficacy and are often associated with undesirable side effects. A major hurdle to developing new therapies for AGA is the lack of small animal models to support drug discovery research. Here, we report the first rodent model of AGA. Previous work demonstrating that the interaction between androgen-bound AR and beta-catenin can inhibit Wnt signaling led us to test the hypothesis that expression of AR in hair follicle cells could interfere with hair growth in an androgen-dependent manner. Transgenic mice overexpressing human AR in the skin under control of the keratin 5 promoter were generated. Keratin 5-human AR transgenic mice exposed to high levels of 5alpha-dihydrotestosterone showed delayed hair regeneration, mimicking the AGA scalp. This effect is AR mediated, because treatment with the AR antagonist hydroxyflutamide inhibited the effect of dihydrotestosterone on hair growth. These results support the hypothesis that androgen-mediated hair loss is AR dependent and suggest that AR and beta-catenin mediate this effect. These mice can now be used to test new therapeutic agents for the treatment of AGA, accelerating the drug discovery process.
Asunto(s)
Alopecia/metabolismo , Modelos Animales de Enfermedad , Alopecia/tratamiento farmacológico , Alopecia/genética , Antagonistas de Andrógenos/farmacología , Andrógenos/farmacología , Animales , Western Blotting , Línea Celular , Línea Celular Tumoral , Dihidrotestosterona/farmacología , Femenino , Flutamida/análogos & derivados , Flutamida/farmacología , Cabello/efectos de los fármacos , Cabello/crecimiento & desarrollo , Cabello/metabolismo , Humanos , Queratina-5/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Regiones Promotoras Genéticas/genética , Unión Proteica , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Transfección , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Progesterone receptor (PR) agonists have several important applications in women's health, such as in oral contraception and post-menopausal hormone therapy. Currently, all PR agonists used clinically are steroids. Because of their interactions with other steroid receptors, steroid-metabolizing enzymes, or other steroid-signaling pathways, these drugs can pose significant side effects in some women. Efforts to discover novel nonsteroidal PR agonists with improved biological properties led to the discovery of tanaproget (TNPR). TNPR binds to the PR from various species with a higher relative affinity than reference steroidal progestins. In T47D cells, TNPR induces alkaline phosphatase activity with an EC(50) value of 0.1 nm, comparable with potent steroidal progestins such as medroxyprogesterone acetate (MPA) and trimegestone (TMG), albeit with a reduced efficacy ( approximately 60%). In a mammalian two-hybrid assay to measure PR agonist-induced interaction between steroid receptor co-activator-1 and PR, TNPR showed similar potency (EC(50) value of 0.02 nm) and efficacy to MPA and TMG. Importantly, in key animal models such as the rat ovulation inhibition assay, TNPR demonstrates full efficacy and an enhanced progestational potency (30-fold) when compared with MPA and TMG. Furthermore, TNPR has relatively weak interactions with other steroid receptors and binding proteins and little effect on cytochrome P450 metabolic pathways. Finally, the three-dimensional crystal structure of the PR ligand binding domain with TNPR has been delineated to demonstrate how this nonsteroidal ligand achieves its high binding affinity. Therefore, TNPR is a structurally novel and very selective PR agonist with an improved preclinical pharmacological profile.
Asunto(s)
Benzoxazinas/agonistas , Pirroles/agonistas , Receptores de Progesterona/agonistas , Fosfatasa Alcalina/metabolismo , Sustitución de Aminoácidos , Sitios de Unión , Neoplasias de la Mama , Línea Celular Tumoral , Humanos , Ligandos , Mutagénesis Sitio-Dirigida , Promegestona/análogos & derivados , Promegestona/farmacología , Receptores de Progesterona/química , Receptores de Progesterona/genética , Proteínas Recombinantes/agonistas , Difracción de Rayos XRESUMEN
Inflammation is now recognized as a key component in a number of diseases such as atherosclerosis, rheumatoid arthritis, and inflammatory bowel disease. The transcription factor NF-kappaB has been shown to be involved in both the early and late stages of the inflammatory-proliferative process. In this report, we describe the identification of the pathway-selective estrogen receptor (ER) ligand, WAY-169916, that inhibits NF-kappaB transcriptional activity but is devoid of conventional estrogenic activity. This pathway-selective ligand does not promote the classic actions of estrogens such as stimulation of uterine proliferation or ER-mediated gene expression, but is a potent antiinflammatory agent, as demonstrated in the HLA-B27 transgenic rat model of inflammatory bowel disease. Our results indicate the potential utility of pathway-selective ER ligands such as WAY-169916 in the treatment of chronic inflammatory diseases.