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![Conversion of antagonist to agonist, elimination of mutagenic potential, and various hydantoin replacements. Bristol-Myers Squibb (BMS) extensively explored antagonist templates and demonstrated the conversion of antagonist templates into agonist templates using a fragmentation approach. This group also explored several [5.5] bicyclic templates as alternatives to their [5.5] bicyclic hydantoin template of BMS-564929 (29). BMS-564929 (29) was characterized as a high potency myoanabolic SARM with high in vivo selectivity as related to the prostate, but a relatively narrow therapeutic index with regard to LH suppression. BMS licensed their SARM program to Pharmacopeia Drug Discovery, including BMS-564929 (29) (now PS178990).](profile/Michael-Mohler-2/publication/23660443/figure/fig4/AS:394434802929664@1471051993304/Conversion-of-antagonist-to-agonist-elimination-of-mutagenic-potential-and-various.png)
Conversion of antagonist to agonist, elimination of mutagenic potential, and various hydantoin replacements. Bristol-Myers Squibb (BMS) extensively explored antagonist templates and demonstrated the conversion of antagonist templates into agonist templates using a fragmentation approach. This group also explored several [5.5] bicyclic templates as alternatives to their [5.5] bicyclic hydantoin template of BMS-564929 (29). BMS-564929 (29) was characterized as a high potency myoanabolic SARM with high in vivo selectivity as related to the prostate, but a relatively narrow therapeutic index with regard to LH suppression. BMS licensed their SARM program to Pharmacopeia Drug Discovery, including BMS-564929 (29) (now PS178990).
Source publication
Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anab...
Contexts in source publication
Context 1
... of the diversity within the patented AR ligand template portfolio have been recently reviewed [Mohler et al., 2008]. The A-rings are typically naphthyl or trisubstituted phenyl aniline derivatives (representative examples in Figure 5). BMS reported mutagenicity associated with the naphthyl aniline hydrolytic metabolites and the ability to design out these problems using trisubstituted phenyl A-rings which are para cyano/nitro, meta halogen and ortho methyl anilines . ...
Context 2
... BMS explained how to convert certain of their antagonists into agonists with SARM activity [Sun et al., 2006]. Figure 5 illustrates how BMS obtained potent and selective SARM activity by simplifying the B-ring to a [5.5] bicyclic hydantoin, which has a hydroxyl substituent properly located to interact with N705 (contrast (25b) and (26)). ...
Context 3
... addition to optimizing the aryl aniline (i.e., A-ring) portion of their SARMs, BMS has also explored variants of the [5.5] hydantoin ring system (i.e., B-ring), as illustrated in Figure 5 (middle). The optimal molecule in each case has the same p-CN, m-Cl, and o-methyl substituted aniline A-ring (i.e., optimized to be non-mutagenic), which provides the desired 58-62° aryl ring to hydrantoin ring dihedral angle . ...
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... the stereochemistry of the hydroxyl group is very important for binding affinity and in vitro activity. The most potent and selective compound, (27) in Figure 5, was characterized as a tissue-selective partial myoanabolic agonist in a restorative in vivo assay (i.e., waiting period to allow diminution of tissues between castration and treatment). ...
Context 5
... second hydantoin variant (represented by (28) in Figure 5) involves the replacement of one of the C=O groups of the hydantoin moiety with small alkyl groups, forming an imidazolin-2-one-containing [5.5] ring system. This design concept emerged from crystallographic studies which demonstrated that this C=O makes no direct contacts with the AR, and may be replaced with a hydrophobic group [Li et al., 2007]. ...
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... these results (and similar templates from Johnson & Johnson, as discussed infra) suggest that the AR is tolerant to a wide variety of rigidified [5.5] is a potent and hyperanabolic agonist compared to testosterone in skeletal muscle (LA) with an efficacy of 125% (comparable to other SARMs) and high potency (ED 50 = 0.0009 mg/kg), with hypostimulation of the prostate relative to testosterone (ED 50 = 0.14 mg/kg). As illustrated in Figure 5, these experiments in castrated rats demonstrated a 160-fold selectivity for LA compared to prostate, which they characterized as 'unprecedented muscle vs. prostate selectivity.' However, BMS may have over-estimated the selectivity of their compound, as evidenced by irregularities in the dose response curves and size of the prostate and LA muscle in castrated rats. ...
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Several testosterone preparations are used in the treatment of hypogonadism in the ageing male. These therapies differ in their convenience, flexibility, regional availability and expense but share their pharmacokinetic basis of approval and dearth of long-term safety data. The brevity and relatively reduced cost of pharmacokinetic based registrati...
Citations
... Non-steroidal SARMs were discovered later and are grouped into different classes. The first class to be discovered was the arylpropionamides (Bhasin 2015;Narayanan et al. 2008). Nowadays, the non-steroidal group of modulators is more relevant, as its representatives exhibit weaker androgenic effects in addition to the pronounced anabolic effects known from the steroidal group. ...
The purpose of this study is to study the effects of ostarine alone and in combination with endurance training in sexually mature, male Wistar rats. The rats were divided into a treadmill-trained group and a sedentary group. Half of each group received either ostarine or vehicle for 8 weeks (n = 10 each, in total n = 40). We examined some functional, hormonal, and anthropometric parameters and the myogenic gene expression of myostatin, insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factor-A (VEGF-A) in m. gastrocnemius. Ostarine decreased submaximal endurance and increased myogenic gene expression of myostatin but had no effect on maximal time to exhaustion and grip strength. Training increased submaximal endurance, maximal time to exhaustion, and grip strength. Our results indicate that both exercise and ostarine treatment had no significant effects on serum levels of luteinizing hormone, follicle-stimulating hormone, and testosterone, or on the myogenic gene expression of IGF-1 and VEGF-A. Neither ostarine nor the training had a significant effect on the testis, liver, and heart weights. In conclusion, ostarine had no effect on anthropometric and hormonal parameters but increased the myostatin gene expression in muscle. The SARM treatment decreased submaximal endurance without affecting maximal time to exhaustion, and training increased both metrics.
... The non-steroidal forms of SARMs were discovered in the late 1990s, originally demonstrating potential to treat muscle wasting in patients with cancer, osteoporosis, advanced age, and other chronic illnesses [1]. The potential to slow the functional decline of older individuals using targeted androgen signaling has led to the development of nonsteroidal SARMs from nearly all major pharmaceutical companies [2]. Clinical trials, in vivo, and in vitro studies suggest that SARMs can build muscle mass, much like androgenic-anabolic steroids [3][4][5][6][7]. ...
Objectives:
Selective Androgen Receptor Modulators (SARMs) social media interest is at an all-time high. The aim of this study is to analyze the: (1) quality; (2) educational content; and (3) reliability of the most relevant YouTube videos on SARMs to explain growing SARMs abuse by recreational and professional athletes.
Methods:
'SARMs' was queried (November 28, 2021) through the YouTube video library. The top 100 videos filtered by relevance were categorized by source, type of content, educational quality by Global Quality Score (GQS), reliability by Journal of American Medicine Association (JAMA) criteria, YouTube tags, attitude towards SARMs use, and whether the video provided specific support on how to use SARMs. For all outcome variables, descriptive statistics and comparison among source types and category types were performed.
Results:
Mean JAMA score was 1.6 ± 0.7 out of 4. Mean GQS score was 2.5 ± 1.1 out of 5. Patient videos were of lower educational quality than athletic trainer videos (GQS: 2.11 ± 0.95 vs. 2.95 ± 1.00, p < 0.01), and videos categorized as user experience were of lower educational quality than videos categorized as general SARMs information (GQS: 1.92 ± 0.90 vs. 2.72 ± 1.07, p < 0.05). User experience and dosing recommendation videos were statistically significantly more positive in attitude than both general SARMs information and SARMS vs. other PEDs.
Conclusion:
Quality, content, and reliability of SARMs YouTube videos was low. Social media likely causes SARMs abuse through disseminating biased SARMs misinformation. These results serve to educate public health oversight bodies, healthcare providers, and sports team members to better identify signs of SARMs abuse, and promote discussion to discourage SARMs abuse.
... Although the focus on the development of drugs to treat prostate cancer has been on competitive antagonists like flutamide that compete with androgens for binding to the AR ligand binding domain (LBD), many efforts have shifted to developing drugs that target the N-terminal domain (NTD) rather than the LBD. These include chemicals that function as SARDs or inhibit nuclear AR localization by interacting with specific sites on the NTD (Mohler et al., 2021;Narayanan et al., 2008). Although PFQ may function as a SARD, PFQ also does antagonize the effects of dihydrotestosterone in vitro, albeit at high concentrations (Gray et al., 2019a). ...
Administration of individual chemicals and mixtures during sexual differentiation that disrupt the androgen signaling pathway can induce reproductive abnormalities in male rats. In the current study, we co-administered the heptafluoroisopropyl pesticide pyrifluquinazon (PFQ), and dibutyl phthalate (DBP) to pregnant rats during sexual differentiation of the reproductive tract. Both chemicals have been shown to disrupt reproductive tract differentiation in a dose-related manner reducing male anogenital distance (AGD), permanently reducing androgen-dependent tissue weights and sperm counts, and inducing reproductive malformations in male offspring, albeit by different mechanisms of action that converge downstream in the androgen signaling pathway on a common key event. Rats were orally dosed from gestation days 14-18 with dilutions of PFQ and DBP at 0, 12.5, 25, 50, 75 and 100% of the top dose (100 mg/kg PFQ and 750 mg/kg DBP). The mixture ratio was selected such that each chemical would contribute equally to multiple effects on the male offspring reproductive tract and the dose range was designed to determine if the mixture produced additive effects predicted by dose addition or response addition models, or whether significant interactions occurred. Observed data were compared to dose and response addition model predictions. As hypothesized, the mixture reduced F1 male AGD, reproductive organ weights and sperm counts and induced hypospadias with dose addition consistently providing a better prediction of the observed effects than response addition. These results support our hypothesis that chemicals that disrupt the androgen signaling pathway induce dose-additive male reproductive abnormalities regardless of the specific mechanism of action.
... In recent years, Ligand Pharmaceuticals were the first to develop a SARM with anabolic activity on skeletal muscle and some degree of tissue selectivity. Two decades since these early efforts, we have witnessed the emergence of a large number of nonsteroidal SARMs from virtually all major pharmaceutical companies but there has been little success in bringing an FDA approved product to market [2]. Furthermore, the success of SERMs such as clomiphene, which now plays an important role in treating both male and female infertility, has reignited interest in SARMs [3]. ...
Selective androgen receptor modulators (SARMs) are a class of androgen receptor ligands that bind androgen receptors and display tissue selective activation of androgenic signaling. SARMs have selective anabolic effects on muscle and bone, and were originally synthesized for treatment of muscle wasting conditions, osteoporosis, breast cancer. To date, no SARM has been clinically approved and little is known about the beneficial effects and other adverse effects on users. We examined the adverse effects and potential benefits of SARMs amongst users. We performed an internet survey assessing the demographics of users via a 32-question survey. Using reddit as a platform, we distributed the survey through various subreddits that included potential SARMs users. Out of the 520 responses, 343 participants admitted having used SARMs. Most were males (98.5%), between the ages of 18–29 (72.3%). More than 90% of users acquired SARMs via the internet and did not consult with a physician. More than half of SARMs users experienced side effects including mood swings, decreased testicular size, and acne. More than 90% of men reported increased muscle mass and were satisfied with their SARMs usage. Despite having seemingly positive effects, more than 50% of SARMs users report significant adverse effects. Chi square was the main method of statistical analysis. Future studies should focus on comprehensive reproductive evaluation of men using SARMs.
... In 1998, bicalutamide was introduced, the first drug from the SARM group -the androgen receptor antagonist. [246,247] Androgen receptor agonists are currently undergoing intensive research. Presently, they have been shown to have the ability to stimulate muscle growth, allow bone reconstruction, and reduce body fat. ...
... In the future, SARMs may prove to be promising agents in the treatment of hypogonadism, osteoporosis, prostate hypertrophy, and muscle loss (cachexia) in the course of cancer or sarcopenia. [246,247] On the basis of the conducted research, it was found that no structure classified as an SARM agonist was approved for use in pharmacotherapy. Most SARMs agonists have been tested in vitro or in animal models. ...
... Most SARMs agonists have been tested in vitro or in animal models. [246,247] Few of them, marked with symbols S-4 and S-22, were included in clinical trials. Clinical research on the S-4 compound was suspended due to adverse effects -blurred vision. ...
... In 1998, bicalutamide was introduced, the first drug from the SARM group -the androgen receptor antagonist. [246,247] Androgen receptor agonists are currently undergoing intensive research. Presently, they have been shown to have the ability to stimulate muscle growth, allow bone reconstruction, and reduce body fat. ...
... In the future, SARMs may prove to be promising agents in the treatment of hypogonadism, osteoporosis, prostate hypertrophy, and muscle loss (cachexia) in the course of cancer or sarcopenia. [246,247] On the basis of the conducted research, it was found that no structure classified as an SARM agonist was approved for use in pharmacotherapy. Most SARMs agonists have been tested in vitro or in animal models. ...
... Most SARMs agonists have been tested in vitro or in animal models. [246,247] Few of them, marked with symbols S-4 and S-22, were included in clinical trials. Clinical research on the S-4 compound was suspended due to adverse effects -blurred vision. ...
This review focuses on four new product categories of food supplements: pre‐workout, fat burner/thermogenic, brain/cognitive booster, and hormone/testosterone booster. Many food supplements have been shown to be contaminated with unauthorized substances. In some cases, the ingredients in the new categories of dietary supplements were medicinal products or new synthetic compounds added without performing clinical trials. Some of the new ingredients in dietary supplements are plant materials that are registered in the pharmacopoeia as herbal medicines. In other cases, dietary supplements may contain plant materials that have no history of human use and are often used as materials to “camouflage” stimulants. In the European Union, new ingredients of dietary supplements, according to European Food Safety Authority or unauthorized novel food. Furthermore, selected ingredients in dietary supplements may be prohibited in sports and are recognized as doping agents by World Anti‐Doping Agency.
... Currently, there are cycles where athletes use drugs known as selective androgen receptor modulators (SARMs), such as ostarine (enobosarm), andarine, testolone, and ligandrol (cardarine and ibutamoren are marketed as SARMs but these substances have different mechanisms). These drugs would be non-hormonal options to the AAS and act as agonists of the androgen receptor (main binding protein of the AAS) and are often used experimentally or with indication for situations such as stress urinary incontinence and cachexia related to a specific type of diseases such as breast cancer and chronic obstructive pulmonary disease [35][36][37]. The use of this class of products has been growing because there is a collective concept, without scientific basis, that they are safer in relation to AAS and do not present adverse reactions, mainly related to androgenization, besides their sale being facilitated by the internet, since many are still being tested or even abandoned by the original laboratories [38]. ...
... There is a vast amount of literature that describe how herbal products can be contaminated by drugs and other agents, as well as problems involving dosages and other issues that can be harmful to the final user [36,51,52]. Therefore, the pharmacist's role in this case is essential to avoid unnecessary drug-related problems and to promote a rational use of these products, evaluating dosages and formulations, in order to detect and prevent harmful situations that can arise from the inappropriate use of herbal and dietary supplements. ...
Pharmaceutical care in sports is a new field of work to clinical pharmacists, focused on promoting pharmacotherapeutic follow up and clinical services to athletes, physical activity practitioners and enthusiasts of any sports modality. A broad range of pharmaceuticals, dietary supplements and herbal drugs have been used historically as performance promoters, doping or ergogenic aids. In this context, the role of pharmacists in prevent adverse events, drug interactions or any drug related problems, as doping issues, was described. Its actions can be important to contribute with a multi professional clinical health team, leading athletes to use these resources in a rational way, promoting and optimizing the therapeutic when its necessary.
... Piñero et al. found that yohimbine diminished tumor growth in vitro, and it was associated with inhibition of ERK1/2 phosphorylation in vivo [61]. It was also proved that α-yohimbine could reverse tumor growth after stimulation with clonidine in vivo [59]. Additionally, Flint et al. demonstrated that MDA-MB-231 cells developed resistance to paclitaxel when treated in combination with catecholamines and/or cortisol [60]. ...
Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer which presents a high rate of relapse, metastasis, and mortality. Nowadays, the absence of approved specific targeted therapies to eradicate TNBC remains one of the main challenges in clinical practice. Drug discovery is a long and costly process that can be dramatically improved by drug repurposing, which identifies new uses for existing drugs, both approved and investigational. Drug repositioning benefits from improvements in computational methods related to chemoinformatics, genomics, and systems biology. To the best of our knowledge, we propose a novel and inclusive classification of those approaches whereby drug repurposing can be achieved in silico: structure-based, transcriptional signatures-based, biological networks-based, and data-mining-based drug repositioning. This review specially emphasizes the most relevant research, both at preclinical and clinical settings, aimed at repurposing pre-existing drugs to treat TNBC on the basis of molecular mechanisms and signaling pathways such as androgen receptor, adrenergic receptor, STAT3, nitric oxide synthase, or AXL. Finally, because of the ability and relevance of cancer stem cells (CSCs) to drive tumor aggressiveness and poor clinical outcome, we also focus on those molecules repurposed to specifically target this cell population to tackle recurrence and metastases associated with the progression of TNBC.
... Selective androgen receptor modulators (SARMs) were developed to overcome the side effects and the poor oral bioavailability and pharmacokinetic profile of testosterone (20,21). While the exact mechanism of the action of SARMs is not fully understood, the key reason for higher tissue specificity and more favorable pharmacokinetics is considered to be their resistance to aromatization or 5-α-reduction (22,23). Ostarine (OS) (enobosarm, S-22, MK-2866, or GTx-024) and Ligandrol (LG) (LGD-4033, VK5211) are both non-steroidal SARMs. ...
In postmenopausal women, hormonal decline changes muscle function and structure. The non-steroidal selective androgen receptor modulators (SARMs) Ostarine (OS) and Ligandrol (LG) have been shown to increase muscle mass and physical function while showing a relative low risk profile. Information about their effects on muscle structure and metabolism is lacking. To analyze this, two experiments were performed using ovariectomized rats as a standard model for postmenopausal conditions. In each experiment, 3-month old Sprague-Dawley rats were divided into five groups (n = 12 to 15). One group remained intact (Non-OVX), the other four groups were ovariectomized (OVX) and remained untreated for eight (OS Experiment) or nine (LG Experiment) weeks. Thereafter, rats of three of the four OVX groups were treated with OS or LG (with doses of 0.04, 0.4, or 4 mg/kg body weight/day) for 5 weeks. Then, uterus, gastrocnemius, and soleus muscles were weighed, fiber size, capillary density, and enzyme activity (lactate dehydrogenase [LDH], citrate synthase [CS], and complex I) were analyzed. In the LG experiment, intramuscular fat content was determined in the quadriceps femoris muscle. All OS treatments resulted in a higher capillary density in the gastrocnemius and longissimus muscles compared with the Non-OVX and the OVX rats, whereas all LG treatments showed a higher capillary density compared with the Non-OVX group. Muscle fiber size and distribution patterns were not changed under either SARM. The CS activity was higher in the longissimus muscle under OS treatment. LG resulted in a higher activity of CS in the gastrocnemius and of LDH in the longissimus muscle. Both SARMs showed an uterotrophic effect, OS at 4 and 0,4 mg dosages, LG at 4 mg dosage. In sum, beneficial effect on muscle vascularization was observed for both SARMs with a stronger impact for OS. LG showed more effect on muscle metabolism. However, a higher muscle weight and intramuscular fat content observed after LG treatment (4 mg) as well as an uterotrophic effect of both SARMs at higher dosages could be considered as an unfavorable side effects and might be a limitation for their application at these dosages.
... The basic idea of the SARMs is that they modulate the transcriptional activity of the androgen receptor in a tissue-selective fashion. [8][9][10][11][12] Although the efficacy of SARMs for peripheral tissues such as muscle is well established, the extent to which SARMs exert protective androgen effects in the brain is unclear. 13,14 Several nonsteroidal selective androgen receptor agonists that are under preclinical or clinical development have been reported; several of these compounds have revealed potent and useful anabolic activity and acted as partial agonists in androgenic tissues in animal models. ...
ACP‐105 is a novel non‐steroidal selective androgen receptor modulator (SARM) with a tissue‐specific agonist effect and does not have side effects associated with the use of common androgens. This research, reports a comprehensive study for the detection of ACP‐105 and its metabolites in racehorses after oral administration (in vivo) and postulating its structures using mass spectrometric techniques. To obtain the metabolic profile of ACP‐105, a selective and reliable LC‐MS/MS method was developed. The chemical structures of the metabolites were determined based on their fragmentation pattern, accurate mass, and retention time. Under the current experimental condition, a total of nineteen (19) metabolites were detected in ACP‐105 drug administered equine urine samples. The study results suggest the following: (1) ACP‐105 is prone to oxidation, which gives corresponding mono, di, and trihydroxylated metabolites, (2) along with oxidation, there is a possibility of elimination of water molecule (dehydration) from the 3rd position of the tropine moiety, resulting in the dehydrated analogs of corresponding mono, di, and trihydroxylated metabolites, (3) from the study on the metabolites using LC‐MS/MS, it is clear that the fragmentation pattern is identical and a great number of fragment ions are common in all the metabolites and the parent drug. (4) The ACP‐105 and its metabolites were detected for up to 72 hrs, thus the result is a valuable tool for evaluating its use and/or misuse in sport.
