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.

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) ␤ as an important regulator of metabolic diseases. However, the potential of ER-␤-selective ligands to offset obesity is not clear. We evaluated the pharmacological effect of ER-␤-selective ligands (␤-LGNDs) in animal models of high-fat diet-and ovariectomyinduced obesity. Ligand binding, transactivation, and uterotrophic studies with ␤-LGNDs demonstrated selectivity for ER-␤ over ER-␣. Animals fed a high-fat diet showed a significant increase in body weight, and this weight gain was attenuated by ␤-LGNDs. High-fat diet-mediated increases in serum cholesterol, leptin, glucose, and fat accumulation in organs were also reduced by ␤-LGNDs. In addition, MRI scanning indicated that ␤-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 ␤-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 ␤-LGNDs were due to indirect peroxisome proliferator-activated receptor ␥ antagonistic actions requiring the ligand binding domain of ER-␤ and through abrogation of the ability of PGC-1 to coactivate peroxisome proliferator-activated receptor ␥. In conclusion, these studies indicate that ligand-activated ER-␤ is a potential therapeutic target to combat obesity and obesity-related metabolic diseases.Obesity is an epidemic disease affecting over 400 million people globally (1). Two-thirds of adults and children in the United States are either overweight or obese, making it a serious health risk and economic burden to society (2). Obesity is not a standalone disease, as its emergence leads to various complications, including type 2 diabetes mellitus (T2DM), 3 hypertension, atherosclerosis, and other cardiovascular diseases, osteoporosis, and clinical depression (3, 4). The United States Food and Drug Administration required an anti-obesity drug to reduce the body weight by 5% and/or better results than placebo in 12 months, indicating that even a marginal reduction in body weight will cause a significant improvement in the welfare of these patients (5). Despite the exponentially growing global obesity pharmaceutical market, only two Food and Drug Administration-approved drugs are available for this indication: 1) amphetamines and sibutramine that act on the hypothalamus to control appetite stimulation in the central nervous system, and 2) Orlistat, which is a lipase inhibitor that blocks gastrointestinal absorption of fat and decreases energy uptake (6). Despite mediocre performance, these drugs are commonly associated with side effects such as tachycardia, hypertension, fecal incontinence, ...

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.

Purpose-This study was conducted to examine the bone and body composition effects of S-4, an arylpropionamide 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.