Despite evidenced clinical and preclinical studies, no SARM has yet received full clinical approval. However, the enormous anabolic properties of SARM muscles and bones give rise to potential misuse in sports, as has been recognized by the World Anti-Doping Agency (WADA), which has included SARM in the banned list released annually since 2008 (class S1.2, other anabolic agents) [45].
Due to its considerable variety of central chemical structure and the display of substantially different physical and chemical properties, the generation of SARM data related to ionization and dissociation of substances under analytical conditions commonly used in doping control laboratories is crucial for routine testing of sports drugs. Therefore, drug candidates have been subjected to electrospray ionization, high-resolution mass spectrometry, and electron ionization, to reveal structural information that supports the development of test methods and metabolism studies [46].
In this context, LGD-4033 (also known as VK5211, Ligandrol or Anabolicum) (4 - ((R)-2-((R)-2,2,2-trifluoro-1-hydroxyethy1) pyrrolidine-1-y1) -2-trifluoro-methyl) benzonitrile) is a SARM with a central structure of pyrrolidinyl-benzonitrile [47]. A study in young, healthy men proved that LGD-4033 is safe, well-tolerated, has a favorable pharmacokinetic profile with a prolonged elimination half-life (24-36 hours), in addition to showing increased lean body mass. Longer randomized studies should assess its effectiveness in improving physical function and health benefits. Although its use is not officially approved and is not yet manufactured by a pharmaceutical company, many websites make LGD-4033 widely available and studies have reported its detection in black market products [47].
A study of LGD-4033 metabolism in human urine, as well as in a doping control sample from a human athlete, has been reported. The metabolites of microsomes by the human liver, as well as electrochemical conversion metabolites / microbial degradation of LGD-4033 have also been described [47].
GlaxoSmithKline (GSK) 2881078 is a selective non-steroidal SARM modulator under investigation by GSK for the treatment of reduced mobility and other functional limitations in men and women with muscle weakness associated with chronic and acute diseases [48]. Thus, in a human study, we report the safety, tolerability, pharmacokinetics, and pharmacodynamics of SARM GSK2881078. In part A, healthy young men (n = 10) received a single dose of the study drug (0 mg, 0.05 mg, 0.1 mg, 0.2 mg gsk2881078 or corresponding placebo). In part b, the cohorts of repeated doses in men (n = 65) were 0.05 mg, 0.2 mg and 0.08 mg, 0.24 mg, 0.48 mg, 0.75 mg or placebo; in women (n = 24) it was 0.24 mg, 0.35 mg or placebo (7 days for 0.5 mg, 14 days for other doses). Pharmacokinetic analysis showed dose-proportional increases in exposure and a long half-life> 100 h. There were no significant effects on vital signs, electrocardiograms, cardiac telemetry, or standard clinical laboratory studies. A dose-response effect was observed in the reduction of high-density lipoprotein and sex hormone-binding globulin. In women with 0.35 mg, the differences from placebo were -0.518 (95% confidence interval: -0.703, -0.334) mmol l-1 and -39.1 (-48.5, -29.7 ) nmol l-1, respectively. Women showed greater sensitivity to these parameters at lower doses than men. Adverse drug-related events were mild. One woman developed a rash and was removed. Two men had elevated creatine phosphokinase after physical exertion during follow-up. Therefore, these data demonstrated pharmacodynamic effects with acceptable tolerability and support an additional clinical assessment of this SARM [48].
Still, another phase 1b study aimed at exploring, over a range of doses, the pharmacokinetic relationship and more safety and tolerability data for gsk2881078 [49]. This study also evaluated the effects of cyp3a4 inhibition on the pharmacokinetics of gsk2881078. This study followed a randomized, placebo-controlled, parallel-group, repeated dose, and dose escalation model in older healthy men and postmenopausal women. Three male and three female cohorts were studied. Dosing at each dose level was twice daily for the first 3 days, followed by once daily for up to 53 days. Repeated x-ray absorptiometry and magnetic resonance imaging were performed in the cross-section of the thigh. The effect of cyp3a4 inhibition on gsk2881078 was evaluated in a separate cohort. The gsk2881078 was generally well tolerated and no serious adverse events were reported. Compared with the placebo, there was a greater accumulation of lean mass with all dose levels of gsk2881078. Women exhibited a greater response at lower doses than men. Transient elevations of alanine aminotransferase were observed. The effect of cyp3a4 inhibition on gks2881078 is likely to have no clinical significance. Therefore, gsk2881078 produced dose-dependent increases in lean mass, with evidence of greater sensitivity in women. The compound was well tolerated [49].
Also, the assembly of inflammasomes after infection or injury leads to the release of interleukin-1β (IL-1β) and pyroptosis. After activation of the inflammasome, the pyroptosis cells either enter a hyperactive state defined by the secretion of IL-1β without cell death. The removal of the toll-il-1r SARM protein from macrophages decouples the release of inflammasome-dependent cytokines and pyroptosis, in which cells exhibit increased production of IL-1β, but reduce pyroptosis in the same way. The increase in sarm in the cells caused less release of IL-1β and pyroptosis. SARM suppressed IL-1β by directly restricting the nlrp3 inflammasome and, therefore, caspase-1 activation [50].
A steroid compound was recently detected as (17α, 20e) -17.20 - [(1-methoxyethylidene) bis (oxy)] - 3-oxo-19-norpregna-4,20- diene-21-carboxylic acid methyl ester (yk11). This compound is described as having selective properties of androgen receptor modulators and myostatin inhibitor. As yk11 is an experimental drug candidate and an unapproved substance for humans, scientific data on its metabolism is scarce. Due to its steroid backbone and the undisputably labile derived orthoester portion, positioned in the d ring, substantial in vivometabolic conversion was anticipated [51].
Also, RA has attracted attention in the treatment of breast cancer. Due to the undesirable side effects of ar agonists, attempts have been made to develop selective RA modulators. Thus, one of these compounds is cl-4as-1. three different breast cancer cell lines were used, namely, mcf-7 luminal cells, mda-mb-453 apocrine molecular cells, and triple-negative basal cells, mda-mb-231. The high and significant agreement was found between dihydrotestosterone (DHT) and cl-4as-1 in the regulation of gene expression in mda-mb-453 cells. however, some differences were observed, including the expression of RA, which was regulated by DHT, but not by cl-4as-1. Also, DHT and cl-4as-1 caused a similar morphological change and reorganization of the actin structure of mda-mb-453 cells into a mesenchymal phenotype. Treatment of cells with dht resulted in the induction of the proliferation of mcf-7 and mda-mb-453 cells, but no effect was observed on the growth of mda-mb-231 cells. On the other hand, increasing doses of cl-4as-1 resulted in a dose-dependent inhibition of the growth of the three cell lines. This inhibition was the result of the induction of apoptosis by which cl-4as-1 caused a block in the entry of cells in the s phase, followed by DNA degradation. Therefore, these results indicate that, although cl-4as-1 has characteristics of the classic RA agonist, it has different properties that may make it useful in the treatment of breast cancer [52].
Also, a report described the discovery of RAD140, a potent non-steroidal selective modulator, orally bioavailable, non-selective steroid for RA. The characterization of RAD140 in several preclinical models of anabolic androgen action is also described. RAD140 has excellent pharmacokinetics and is a potent anabolic also in non-human primates. The general preclinical profile of RAD140 completed preclinical toxicology in rats and monkeys. At the moment, RAD140 is being prepared for phase 1 clinical studies in patients suffering from weight loss due to cancer cachexia [53].
In this sense, loss of muscle mass in cancer is a common and often hidden condition that can occur before obvious signs of weight loss and before a clinical diagnosis of cachexia can be made. Muscle wastage in cancer is an important and independent predictor of progressive functional impairment, decreased quality of life and increased mortality. Although several therapeutic agents are currently under development to treat muscle wasting or cachexia in cancer, most of these agents do not directly inhibit muscle wasting. Thus, SARMs have the potential to increase lean body mass and, therefore, muscle mass, without the undesirable side effects seen with traditional anabolic agents [54].
Thus, Enobosarm, a non-steroid SARM, is an agent in the clinical development for preventing and treating muscle wasting in cancer patients (phase 1 and 2 trials). Also, a phase 3, randomized, double-blind, placebo-controlled, multicenter, multinational trial was designed to evaluate the effectiveness of Enobosarm in preventing and treating muscle wasting in individuals who initiate first-line chemotherapy for non-chemotherapy. little. In each study, subjects will receive either placebo (n = 150) or Enobosarm 3 mg (n = 150) orally once daily for 147 days. Physical function, assessed as the power to climb stairs, and lean mass assessed by dual-energy x-ray absorptiometry, are the end points of effectiveness in both tests evaluated on the day. Based on extensive comments from the Food and Drug Administration (FDA), an individual should experience a 10% improvement in physical function compared to the baseline. To meet the definition of response in lean mass, a subject must have demonstrated no loss of lean mass compared to the baseline. Secondary end points include the durability of the assessed response. The efficacy parameters are the result of this feedback and discussion of the threshold for clinical benefit in patients at risk of muscle loss. The full results of these studies will be published shortly [54].
Also, a selective non-steroidal modulator named ly305 has been identified, which is bioavailable through a transdermal route of administration while being highly eliminated by hepatic metabolism to limit the exposure of parent compounds in the liver. The selection of this compound and its transdermal formulation was based on the optimization of skin absorption properties using in vitro and in vivo skin models. This molecule is an agonist of the perineal muscle and is a weak partial agonist of androgenic tissues, such as the prostate. When ly305 was tested on animal models of skeletal atrophy, it restored skeletal muscle mass through accelerated repair. In a model of bone fracture, ly305 remained osteoprotective in the regenerating tissue and without deleterious effects. In a small cohort of healthy volunteers, the safety and tolerability of ly305 was assessed when administered transdermally. Ly305 showed a dose-dependent increase in serum exposure and was well tolerated with minimal adverse effects. Notably, there were no statistically significant changes in hematocrit or HDL after the 4-week treatment period. Collectively, ly305 represents the first of its kind to develop a non-steroidal transdermal SARM with unique properties that may find clinical utility [55].
The gtx-024 (Enobosarm) is the first selective modulator of androgen receptors of the class, being developed for several indications in oncology. Pre-clinical studies of gtx-024 supported the evaluation of several potential drug interactions in a clinical setting. A series of open phase 1 drug interaction studies was designed to interrogate possible interactions with a cyp3a4 inhibitor (itraconazole), a cyp3a4 inducer (rifampicin), a pan-ugt inhibitor (probenid), a cyp2c9 substrate (celecoxib) ) and a bcrp substrate (rosuvastatin). The plasma pharmacokinetics of gtx-024, its main metabolite (glucuronide gtx-024) and each substrate were characterized in detail. Administration of itraconazole did not affect the pharmacokinetics of gtx-024. Likewise, the administration of gtx-024 did not significantly alter the pharmacokinetics of celecoxib or rosuvastatin. Administration of rifampicin had the greatest impact on the pharmacokinetics of gtx-024 of any co-administered agent and reduced the maximum plasma concentration by 23% and the area under the curve by 43%. Probenecid had a complex interaction with gtx-024, so plasma levels of gtx-024 and glucuronide gtx-024 were increased by coadministration of the ugt inhibitor (50 and 112%, respectively). Overall, gtx-024 was well tolerated and has very little risk of generating clinically relevant drug interactions [56].