RESUMEN
Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT improves overall and disease-free survival rates, but long-term therapy is associated with severe side effects of androgen and estrogen depletion including hot flashes, weight gain, depression, and osteoporosis. Effective hormone reduction can be achieved without estrogen deficiency-related side effects by using therapy with estrogenic compounds. However, cardiovascular complications induced by estrogens coupled with the availability of LHRH agonists led to discontinuation of estrogen use for primary androgen deprivation therapy in the 1980s. New treatments for prostate cancer that improve patient outcomes without the serious estrogen deficiency-related toxicities associated with ADT using LHRH analogs are needed. Herein we describe a novel nonsteroidal selective estrogen receptor-α agonist designed for first-line therapy of advanced prostate cancer that in animal models induces medical castration and minimizes many of the estrogen deficiency-related side effects of ADT. The present studies show that orally administered GTx-758 reversibly suppressed testosterone to castrate levels and subsequently reduced prostate volume and circulating prostate-specific antigen in relevant preclinical models without inducing hot flashes, bone loss, thrombophilia, hypercoagulation, or increasing fat mass.
Asunto(s)
Benzamidas/farmacología , Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/metabolismo , Neoplasias de la Próstata/metabolismo , Antagonistas de Andrógenos/farmacología , Animales , Antineoplásicos Hormonales/metabolismo , Composición Corporal , Proliferación Celular , Supervivencia sin Enfermedad , Receptor beta de Estrógeno/metabolismo , Estrógenos/metabolismo , Femenino , Hormona Folículo Estimulante/metabolismo , Humanos , Hormona Luteinizante/metabolismo , Macaca fascicularis , Masculino , Ratas , Testosterona/metabolismo , Activación TranscripcionalRESUMEN
3-(1H-Indol-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone (I-387) is a novel indole compound with antitubulin action and potent antitumor activity in various preclinical models. I-387 avoids drug resistance mediated by P-glycoprotein and showed less neurotoxicity than vinca alkaloids during in vivo studies. We examined the pharmacokinetics and metabolism of I-387 in mice as a component of our preclinical development of this compound and continued interest in structure-activity relationships for antitubulin agents. After a 1 mg/kg intravenous dose, noncompartmental pharmacokinetic analysis in plasma showed that clearance (CL), volume of distribution at steady state (Vd(ss)), and terminal half-life (t(1/2)) of I-387 were 27 ml per min/kg, 5.3 l/kg, and 7 h, respectively. In the in vitro metabolic stability study, half-lives of I-387 were between 10 and 54 min by mouse, rat, dog, monkey, and human liver microsomes in the presence of NADPH, demonstrating interspecies variability. I-387 was most stable in rat liver microsomes and degraded quickly in monkey liver microsomes. Liquid chromatography-tandem mass spectrometry was used to identify phase I metabolites. Hydroxylation, reduction of a ketone group, and O-demethylation were the major metabolites formed by the liver microsomes of the five species. The carbonyl group of I-387 was reduced and identified as the most labile site in human liver microsomes. The results of these drug metabolism and pharmacokinetic studies provide the foundation for future structural modification of this pharmacophore to improve stability of drugs with potent anticancer effects in cancer patients.
Asunto(s)
Antimitóticos/metabolismo , Benzofenonas/metabolismo , Indoles/metabolismo , Microsomas Hepáticos/metabolismo , NADP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Antimitóticos/sangre , Antimitóticos/síntesis química , Antimitóticos/farmacología , Benzofenonas/sangre , Benzofenonas/síntesis química , Benzofenonas/farmacología , Biotransformación , Perros , Estabilidad de Medicamentos , Semivida , Haplorrinos , Humanos , Hidroxilación , Indoles/sangre , Indoles/síntesis química , Indoles/farmacología , Inyecciones Intravenosas , Fase I de la Desintoxicación Metabólica , Fase II de la Desintoxicación Metabólica , Ratones , Microsomas Hepáticos/efectos de los fármacos , Ratas , Especificidad de la Especie , Relación Estructura-ActividadRESUMEN
Formation of microtubules is a dynamic process that involves polymerization and depolymerization of αß-tubulin heterodimers. Drugs that enhance or inhibit tubulin polymerization can destroy this dynamic process, arresting cells in the G(2)/M phase of the cell cycle. Although drugs that target tubulin generally demonstrate cytotoxic potency in the subnanomolar range, resistance due to drug efflux is a common phenomenon among the antitubulin agents. We recently reported a class of 4-substituted methoxybenzoyl-aryl-thiazoles (SMART) that exhibited great in vitro potency and broad spectrum cellular cytotoxicity. Evaluation of the in vitro and in vivo anticancer activities of 3 SMART compounds, SMART-H (H), SMART-F (F), and SMART-OH (OH), with varying substituents at the 4-position of aryl ring, demonstrated that they bind potently to the colchicine-binding site in tubulin, inhibit tubulin polymerization, arrest cancer cells in G(2)/M phase of the cell cycle, and induce their apoptosis. The SMART compounds also equipotently inhibit the growth of parental and MDR-overexpressing cells in vitro, indicating that they can overcome multidrug resistance. In vivo antitumor efficacy studies in human prostate (PC-3) and melanoma (A375) cancer xenograft models demonstrated that SMART-H and SMART-F treatments resulted in %T/C values ranging from 4% to 30%. In addition, in vivo SMART-H treatment for 21 days at the higher dose (15 mg/kg) failed to produce any apparent neurotoxicity. These studies provide the first in vivo evidence and proof-of-concept that SMART compounds are similarly efficacious to currently FDA approved antitubulin drugs for cancer treatment, but they can circumvent P-glycoprotein-mediated drug resistance.
Asunto(s)
Microtúbulos/efectos de los fármacos , Tiazoles/farmacología , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Melanoma/patología , Ratones , Ratones Endogámicos ICR , Neoplasias de la Próstata/patología , Ratas , Ratas Sprague-Dawley , Tiazoles/farmacocinética , Trasplante HeterólogoRESUMEN
Androgen receptor (AR) function is critical for the development of male reproductive organs, muscle, bone and other tissues. Functionally impaired AR results in androgen insensitivity syndrome (AIS). The interaction between AR and microRNA (miR) signaling pathways was examined to understand the role of miRs in AR function. Reduction of androgen levels in Sprague-Dawley rats by castration inhibited the expression of a large set of miRs in prostate and muscle, which was reversed by treatment of castrated rats with 3 mg/day dihydrotestosterone (DHT) or selective androgen receptor modulators. Knockout of the miR processing enzyme, DICER, in LNCaP prostate cancer cells or tissue specifically in mice inhibited AR function leading to AIS. Since the only function of miRs is to bind to 3' UTR and inhibit translation of target genes, androgens might induce miRs to inhibit repressors of AR function. In concordance, knock-down of DICER in LNCaP cells and in tissues in mice induced the expression of corepressors, NCoR and SMRT. These studies demonstrate a feedback loop between miRs, corepressors and AR and the imperative role of miRs in AR function in non-cancerous androgen-responsive tissues.
Asunto(s)
Andrógenos/fisiología , MicroARNs/fisiología , Músculos/fisiología , Próstata/fisiología , Animales , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Humanos , Masculino , Ratones , Reacción en Cadena de la Polimerasa , Ratas , Ratas Sprague-DawleyRESUMEN
Selective androgen receptor modulators (SARMs) have great therapeutic potential in various diseases including cancer cachexia, sarcopenia, and osteoporosis, and the number of drug candidates has been growing over the last decade. The SARM drug candidates S-22 and S-23 belong to one of the most advanced groups of androgen receptor modulators and are based on an arylpropionamide-derived core structure. Due to their anabolic effects, SARMs have been prohibited in elite sports and have been a subject of sports drug testing programmes since January 2008. Consequently, the structure of analytically useful urinary metabolites should be elucidated to provide targets for sensitive and retrospective analysis. In the present study, the phase-I and -II metabolism of S-22 and S-23 was simulated using hepatic human enzymes, and resulting metabolites were characterized by means of state-of-the-art mass spectrometric approaches employing high resolution/high accuracy Orbitrap mass spectrometry. Subsequently, the newly defined target compounds including the glucuronic acid conjugates of S-22 and S-23, their corresponding monohydroxylated and bishydroxylated analogs, as well as their B-ring depleted counterparts were implemented into an existing routine doping control procedure, which was examined for its specificity for the added substances. In order to obtain proof-of-concept data for authentic urine specimens, canine urine samples collected up to 72 h after oral administration of S-22 to dogs were analyzed using the established approach outlining the capability of the presented assay to detect the glucuronide of S-22 as well as the B-ring-depleted metabolite (M3) in all samples following therapeutic (31.4 µg/kg) dosing. Finally, M3 was chemically synthesized, characterized by nuclear magnetic resonance spectroscopy and high resolution/high accuracy mass spectrometry, and chosen as primary target for future doping control analyses.
Asunto(s)
Amidas/metabolismo , Amidas/orina , Anabolizantes/metabolismo , Anabolizantes/orina , Anilidas/metabolismo , Anilidas/orina , Receptores Androgénicos/metabolismo , Animales , Perros , Doping en los Deportes , Humanos , Espectrometría de Masas , Detección de Abuso de SustanciasRESUMEN
Obesity is an epidemic problem affecting millions of people in the Western hemisphere and costs the United States economy more than $200 billion annually. Currently, there are no effective treatments to combat obesity. Recent studies have implicated the constitutive activity of estrogen receptor (ER) ß as an important regulator of metabolic diseases. However, the potential of ER-ß-selective ligands to offset obesity is not clear. We evaluated the pharmacological effect of ER-ß-selective ligands (ß-LGNDs) in animal models of high-fat diet- and ovariectomy-induced obesity. Ligand binding, transactivation, and uterotrophic studies with ß-LGNDs demonstrated selectivity for ER-ß over ER-α. Animals fed a high-fat diet showed a significant increase in body weight, and this weight gain was attenuated by ß-LGNDs. High-fat diet-mediated increases in serum cholesterol, leptin, glucose, and fat accumulation in organs were also reduced by ß-LGNDs. In addition, MRI scanning indicated that ß-LGNDs altered body composition by reducing fat mass and increasing lean body mass. Organ weights and gene expression analyses demonstrated that adipose tissue is the center of action for ß-LGNDs, and the reduction in body weight is likely due to increased energy expenditure. In vitro and in vivo mechanistic studies indicated that the anti-obesity effects of ß-LGNDs were due to indirect peroxisome proliferator-activated receptor γ antagonistic actions requiring the ligand binding domain of ER-ß and through abrogation of the ability of PGC-1 to coactivate peroxisome proliferator-activated receptor γ. In conclusion, these studies indicate that ligand-activated ER-ß is a potential therapeutic target to combat obesity and obesity-related metabolic diseases.
Asunto(s)
Grasas de la Dieta/efectos adversos , Receptor beta de Estrógeno/agonistas , Isoquinolinas/farmacología , Ligandos , Obesidad/tratamiento farmacológico , Ovariectomía , Animales , Glucemia/metabolismo , Colesterol/sangre , Grasas de la Dieta/administración & dosificación , Modelos Animales de Enfermedad , Receptor beta de Estrógeno/metabolismo , Femenino , Leptina/sangre , Masculino , Ratones , Obesidad/sangre , Obesidad/etiología , Tamaño de los Órganos , PPAR gamma/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de Transcripción/metabolismoRESUMEN
PURPOSE: Although androgens are known to protect bone, side effects and poor oral bioavailability have limited their use. We previously reported that S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (S-4) is a potent and tissue-selective androgen receptor modulator (SARM). This study was designed to evaluate the skeletal effects of S-4 in an osteopenic model. METHODS: Aged female rats were gonadectomized or sham operated on day 1 and assigned to treatment groups. Dosing was initiated on day 90 and continued daily until day 210. Whole animal bone mineral density (BMD), body weight, and fat mass were determined by dual energy x-ray absorptiometry (DEXA). Regional analysis of excised bones was performed using DEXA or computed tomography. Femur strength was evaluated by 3-point bending. RESULTS: S-4 restored whole body and lumbar vertebrae (L5-L6) BMD to the level of intact controls. Significant increases in cortical bone quality were observed at the femoral midshaft, resulting in increased load bearing capacity. CONCLUSIONS: S-4 demonstrated partial/complete recovery of bone parameters to age-matched intact levels. Increased efficacy observed in cortical bone sites is consistent with reported androgen action in bone. The ability of S-4 to promote bone anabolism, prevent bone resorption, and increase skeletal muscle mass/strength positions these drugs as promising new alternatives for the treatment of osteoporosis.
Asunto(s)
Andrógenos/farmacología , Quinolinas/farmacología , Receptores Androgénicos/efectos de los fármacos , Animales , Enfermedades Óseas Metabólicas/tratamiento farmacológico , Femenino , Inyecciones Subcutáneas , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Androgen receptor (AR) ligands are important for the development and function of several tissues and organs. However, the poor oral bioavailability, pharmacokinetic properties, and receptor cross-reactivity of testosterone, coupled with side effects, place limits on its clinical use. Selective AR modulators (SARMs) elicit anabolic effects in muscle and bone, sparing reproductive organs like the prostate. However, molecular mechanisms underlying the tissue selectivity remain ambiguous. We performed a variety of in vitro studies to compare and define the molecular mechanisms of an aryl propionamide SARM, S-22, as compared with dihydrotestosterone (DHT). Studies indicated that S-22 increased levator ani muscle weight but decreased the size of prostate in rats. Analysis of the upstream intracellular signaling events indicated that S-22 and DHT mediated their actions through distinct pathways. Modulation of these pathways altered the recruitment of AR and its cofactors to the PSA enhancer in a ligand-dependent fashion. In addition, S-22 induced Xenopus laevis oocyte maturation and rapid phosphorylation of several kinases, through pathways distinct from steroids. These studies reveal novel differences in the molecular mechanisms by which S-22, a nonsteroidal SARM, and DHT mediate their pharmacological effects.
Asunto(s)
Antagonistas de Andrógenos/farmacología , Andrógenos/farmacología , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/fisiología , Amidas/farmacología , Anabolizantes/farmacología , Animales , Secuencia de Bases , Línea Celular , Cartilla de ADN/genética , Dihidrotestosterona/farmacología , Femenino , Humanos , Técnicas In Vitro , Ligandos , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Fosforilación , Ratas , Receptores Androgénicos/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/fisiología , Activación Transcripcional/efectos de los fármacos , Xenopus , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
PURPOSE: This study was conducted to examine the bone and body composition effects of S-4, an aryl-propionamide derived Selective Androgen Receptor Modulator (SARM) in an ovariectomy induced model of accelerated bone loss. METHODS: One hundred twenty female Sprague-Dawley rats aged to twenty-three weeks were randomly assigned to twelve treatment groups. Drug treatment was initiated immediately following ovariectomy and continued for one hundred twenty days. Whole body bone mineral density (BMD), body composition, and lumbar vertebrae BMD were measured by dual energy x-ray absorptiometry. More stringent regional pQCT and biomechanical strength testing was performed on excised femurs. RESULTS: We found that S-4 treatment maintained whole body and trabecular BMD, cortical content, and increased bone strength while decreasing body fat in these animals. CONCLUSIONS: The data presented herein show the protective skeletal effects of S-4. Our previous reports have shown the tissue selectivity and muscle anabolic activity of S-4. Together these data suggest that S-4 could reduce the incidence of fracture via two different mechanisms (i.e., via direct effects in bone and reducing the incidence of falls through increased muscle strength). This approach to fracture reduction would be advantageous over current therapies in these patients which are primarily antiresorptive in nature.
Asunto(s)
Adiposidad/efectos de los fármacos , Conservadores de la Densidad Ósea/uso terapéutico , Osteoporosis Posmenopáusica/prevención & control , Ovariectomía , Receptores Androgénicos/efectos de los fármacos , Absorciometría de Fotón , Acetamidas/uso terapéutico , Aminofenoles/uso terapéutico , Animales , Fenómenos Biomecánicos , Composición Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Dihidrotestosterona/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Osteoblastos/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
The partial agonist activity of a selective androgen receptor modulator (SARM) in the prostate was demonstrated in orchidectomized rats. In the current study, we characterized the full agonist activity of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (a structurally related SARM referred to in other publications and hereafter as S-4) in skeletal muscle, bone, and pituitary of castrated male rats. Twelve weeks after castration, animals were treated with S-4 (3 or 10 mg/kg), dihydrotestosterone (DHT) (3 mg/kg), or vehicle for 8 wk. S-4 (3 and 10 mg/kg) restored soleus muscle mass and strength and levator ani muscle mass to that seen in intact animals. Similar changes were also observed in DHT-treated (3 mg/kg) animals. Compared with the anabolic effects observed in muscle, DHT (3 mg/kg) stimulated prostate and seminal vesicle weights more than 2-fold greater than that observed in intact controls, whereas S-4 (3 mg/kg) returned these androgenic organs to only 16 and 17%, respectively, of the control levels. S-4 (3 and 10 mg/kg) and DHT (3 mg/kg) restored castration-induced loss in lean body mass. Furthermore, S-4 treatment caused a significantly larger increase in total body bone mineral density than DHT. S-4 (3 and 10 mg/kg) also demonstrated agonist activity in the pituitary and significantly decreased plasma LH and FSH levels in castrated animals in a dose-dependent manner. In summary, the strong anabolic effects of S-4 in skeletal muscle, bone, and pituitary were achieved with minimal pharmacologic effect in the prostate. The tissue-selective pharmacologic activity of SARMs provides obvious advantages over steroidal androgen therapy and demonstrates the promising therapeutic utility that this new class of drugs may hold.
Asunto(s)
Acetamidas/farmacología , Aminofenoles/farmacología , Anabolizantes/farmacología , Composición Corporal/efectos de los fármacos , Enfermedades Óseas Metabólicas/etiología , Enfermedades Óseas Metabólicas/prevención & control , Músculo Esquelético/efectos de los fármacos , Orquiectomía/efectos adversos , Receptores Androgénicos/metabolismo , Animales , Densidad Ósea/efectos de los fármacos , Técnicas In Vitro , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiología , Cadenas Pesadas de Miosina/metabolismo , Osteocalcina/sangre , Músculos Papilares/metabolismo , Isoformas de Proteínas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Androgénicos/efectos de los fármacosRESUMEN
Tissue-selective androgen receptor modulators (SARMs) demonstrate tissue selectivity in both castrated and intact male rats, behaving as partial agonists in androgenic tissues (i.e. prostate and seminal vesicle), but full agonists in anabolic tissues (i.e. levator ani muscle). The partial agonist activity of SARMs (compounds S-1 and S-4) in the prostate of intact rats suggested that SARM could be used for androgen suppression in the treatment of benign prostate hyperplasia (BPH). This study was designed to explore the mechanisms of action of SARM and to characterize the tissue selectivity of S-1 in intact male rats compared with that of hydroxyflutamide (antiandrogen) and finasteride (5alpha-reductase inhibitor), two major drugs used for androgen suppression treatment of BPH. In intact male rats, S-1 (5, 10, and 25 mg/kg) selectively decreased the prostate weight with similar efficacy to finasteride (5 mg/kg), without affecting the levator ani muscle or increasing the plasma levels of testosterone, LH, and FSH. Hydroxyflutamide (0.5, 1, 5, 10, and 25 mg/kg), however, decreased both the prostate and levator ani muscle weights without any selectivity and increased plasma hormone levels in a dose-dependent manner. Furthermore, S-1 and S-4 showed very weak inhibitory effects toward transiently expressed type I and II human 5alpha-reductase (Ki, >20 microm) during in vitro assays. Therefore, although S-1 and finasteride showed very similar suppressive effects in the prostate of intact male rats, they decreased prostate size via different mechanisms of action. S-1 simply worked as androgen receptor partial agonist, whereas finasteride inhibited prostatic 5alpha-reductase. These studies indicate that SARMs may demonstrate clinical utility as single agent or combination therapy for BPH.
Asunto(s)
Antagonistas de Andrógenos/farmacología , Inhibidores Enzimáticos/farmacología , Finasterida/farmacología , Flutamida/análogos & derivados , Flutamida/farmacología , Hiperplasia Prostática/tratamiento farmacológico , Receptores Androgénicos/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismo , Inhibidores de 5-alfa-Reductasa , Andrógenos , Animales , Masculino , Próstata/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , TestículoRESUMEN
PURPOSE: The aim of this study was to determine requisite structural features for P-glycoprotein-mediated transport of a series of structurally related glucocorticoids (GCs). METHODS: Transport experiments were conducted in wild-type and stably transfected MDRI LLC-PK cell line. Transport efficiency (Teff = Peff, B-->A / Peff, A-->B) in both cell lines was compared as a measure of passive diffusion and P-glycoprotein-mediated transepithelial transport for each steroid. Three-dimensional structure-activity relationships were built to determine how specific structural features within the steroids affect their P-gp-mediated efflux. RESULTS: Mean (+/- SD) Teff in LLC-PK cells was 1.1 +/- 0.17, indicating that differences in structure and partition coefficient did not affect drug flux in the absence of P-glycoprotein. Teff in L-MDRI cells ranged from 3.6 to 26.6, demonstrating the importance of glucocorticoid structure to P-glycoprotein transport. The rank order of Teff in MDR1 cells was: methylprednisolone> prednisolone > betamethasone > dexamethasone/prednisone > cortisol. There was no correlation between individual Teff values and partition coefficient. 3D-QSAR models were built using CoMFA and CoMSIA with a q2 (r2) of 0.48 (0.99) and 0.41 (0.95), respectively. CONCLUSIONS: Nonpolar bulky substituents around the C-6alpha position, as well as a hydrogen-bond donor at position C-11, enhance P-glycoprotein affinity and cellular efflux, whereas bulky substituents at C-16 diminish transporter affinity.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Glucocorticoides/química , Glucocorticoides/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/biosíntesis , Animales , Transporte Biológico/fisiología , Humanos , Células LLC-PK1 , Ratones , Estructura Molecular , Fenotipo , PorcinosRESUMEN
The present study aimed to identify selective androgen receptor modulators (SARMs) with in vivo pharmacological activity. We examined the in vitro and in vivo pharmacological activity of four chiral, nonsteroidal SARMs synthesized in our laboratories. In the in vitro assays, these compounds demonstrated moderate to high androgen receptor (AR) binding affinity, with K(i) values ranging from 4 to 37 nM, and three of the compounds efficaciously stimulated AR-mediated reporter gene expression. The compounds were then administered subcutaneously to castrated rats to appraise their in vivo pharmacological activity. Androgenic activity was evaluated by the ability of these compounds to maintain the weights of prostate and seminal vesicle, whereas levator ani muscle weight was used as a measure of anabolic activity. The maximal response (E(max)) and dose for half-maximal effect (ED(50)) were determined for each compound and compared with that observed for testosterone propionate (TP). Compounds S-1 and S-4 demonstrated in vivo androgenic and anabolic activity, whereas compounds S-2 and S-3 did not. The activities of S-1 and S-4 were tissue-selective in that both compounds stimulated the anabolic organs more than the androgenic organs. These two compounds were less potent and efficacious than TP in androgenic activity, but their anabolic activity was similar to or greater than that of TP. Neither S-1 nor S-4 caused significant luteinizing hormone or follicle stimulating hormone suppression at doses near the ED(50) value. Thus, compounds S-1 and S-4 were identified as SARMs with potent and tissue-selective in vivo pharmacological activity, and represent the first members of a new class of SARMs with selective anabolic effects.