Description

GSK-2881078 SARM Powder

 

CAS Number	1539314-06-1
Other Names	GSK-2881078, GSK 2881078, GSK2881078
IUPAC Name	1-[(2R)-1-methylsulfonylpropan-2-yl]-4-(trifluoromethyl)indole-5-carbonitrile
Molecular Formula	C₁₄H₁₃F₃N₂O₂S
Molecular Weight	330.33
Purity	≥99% Pure (LC-MS)
Liquid Availability	30mL liquid Glycol (10mg/mL, 300mg bottle)  60mL liquid Glycol (10mg/mL, 600mg bottle)
Powder Availability	1 gram
Gel Availability	10 milligrams
Storage	0º – 4º C for short term (days to weeks) or -20º C for long term (months to years)
Terms	All products are for laboratory developmental research USE ONLY. Products are not for human consumption.

 

What is GSK2881078?

GSK2881078 (1-[(2R)-1-methylsulfonyl propan-2-yl]-4-(trifluoromethyl)indole-5-carbonitrile) is a nonsteroidal, selective androgen receptor modulator (SARM). Current research is being conducted in order to assess the ability of the compound to improve mobility, functional activity, and muscle weakness related to both chronic and acute illnesses.

 

Main Research Findings

1) SARMs have been shown to promote various forms of functional therapy through tissue-selective activation of androgenic signaling.

2) Administration of GSK2881078 resulted in dose-dependent increases in lean muscle mass with no report of extreme side effects.

3) Supplementation of GSK2881078 was well-tolerated and able to increase leg strength in individuals experiencing symptoms of chronic obstructive pulmonary disorder.

Selected Data

1) The research team of Shalender Bhasin, MD and Ravi Jasuja, PhD. examined the potential of selective androgen receptor modulators (SARMs) to promote various forms of functional therapy. Previous research has reported that SARMs bind to androgen receptors and display tissue-selective activation of androgenic signaling, leading to anabolism in skeletal muscles and bones. The actions of SARMs are compared to testosterone, the major ligand for androgen receptors. Testosterone is often supplemented to men and women of all ages suffering from androgen deficiency and decreased muscle and bone wasting. However, administration of androgenic compounds such as testosterone is often related to many dose-limiting adverse side effects such as prostate dysfunction, edema, and erythrocytosis. On the other hand, SARM administration has been shown to result in similar anabolic activity without the adverse side effects associated with typical androgen treatment [1].

In order to target functional limitations caused by osteoporosis, aging, and chronic disorders, researchers first attempted to develop a SARM with the desired activity profile and tissue selectivity. The second approach included elucidating the mechanisms of action of androgens on skeletal muscles and the prostate in order to identify signaling molecules downstream of the androgen receptors that are capable of activating hypertrophic pathways in skeletal muscles but not the prostate. When observing the structure of SARMs, the compounds can be categorized into two groups: steroidal and nonsteroidal. Steroidal SARMs are synthesized by modifying the chemical structure of testosterone molecules. For example, substitution of 7-alpha alkyl makes testosterone less susceptible to 5-alpha reduction, thus increasing tissue selectivity with respect to the prostate. This results in the increased anabolic activity in the levator ani muscle and a decreased rate of anabolism in the prostate and seminal vesicles [1].

2) The research team of Neil et. Al examined how lean muscle mass changed in response to administration of GSK2881078. This experiment was conducted in two parts: Part A was considered a randomized double-blind, placebo-controlled, dose-escalation study in order to evaluate the pharmacokinetics and pharmacodynamics of repeated dose administration of the SARM. Part B was defined as an open-label, single-sequence, two-period crossover study that assessed how inhibition of CYP3A changed the pharmacokinetics of GSK2881078.

Part A utilized healthy postmenopausal females and males over the age of 50; each subject was given a randomized dose of either a placebo compound or an experimental compound, daily, for 28 days. The first two cohorts out of the six cohort volunteers were males and the following two cohorts were females. Males and females were given different doses of their designated compound. The first male cohort received a dose of 0.75 mg while the second male cohort received a dose of 1.5 mg. The first female cohort received a dose of 0.5 mg while the second female cohort received a dose of 0.75 mg. The two remaining cohorts, one female and one male, were administered a dose of the compound, daily, for 56 days rather than 28 days. The females were administered 0.35 mg of the compound for the first 28 days and 1.5 mg for the remaining 28 days while the male subjects received daily administration of a 4 mg dose of GSK2881078 for the complete 56 days [2].

Part B evaluated how the pharmacokinetics of the SARM respond to the inhibition of CYP3A4. One cohort of 15 healthy male subjects was used for this portion of the study; each participant received a single, 0.2 mg dose of GSK2881078 on the first day of the experimental period. Pharmacokinetic samples were collected for 28 days, followed by a 2-week washout period and administration of 200 mg of itraconazole in order to inhibit CYP3A4. The inhibitor was administered twice on the first day of treatment and only once days 2-34. Another 0.2 mg dose of GSK28810978 was administered to the subjects on day 6 and pharmacokinetic samples were collected during the remainder of the second portion of the study.

The safety and tolerability of the SARM was measured through clinical laboratory tests, the monitoring of vital signs through echocardiograms, physical examinations, cardiac biomarkers, and cardiac telemetry, and recording of any instances of adverse side effects. The pharmacokinetic profile of GSK2881078 was evaluated by assaying all collected samples through mass spectrometry analysis, as well as a validated analytical method based on protein precipitation. 50 pg/mL was considered the lower limit of quantification for plasma levels of GSK28110178, while 50,000 pg/mL was defined as the higher limit [2].
Accrual of lean mass was assessed through the use of dual-energy X-ray absorptiometry (DXA), and MRI. DXA scans were used to measure overall body composition as it relates to total lean body mass and appendicular lean body mass. MRI assessed thigh muscle volume both with and without intramuscular fat. The tests were performed on each subject 2 weeks prior to doing, on days 13 to 15 of the 28 day regimen, days 27 to 29 of all regimens, days 55 to 58 of the 56 day regimens, and at the first follow-up visit that took place approximately 2 weeks after the end of the experimental period. In addition to DXA scans and MRIs, liver function tests and plasma levels of lipids and hormones were assessed at baseline, throughout the study, and at the first follow-up visit [2].

3) Skeletal muscle responds favorably to supplementation with SARMs, especially in combination with increased activity levels. The research team of Mohan et. al examined how the combined treatment of GSK2881078 and increased activity affects individuals diagnosed with chronic obstructive pulmonary artery disease (COPD). COPD is typically related to dysfunction of skeletal muscle and a low level of lean body mass and weakness of the quadriceps femoris muscle group is linked to increased rates of morbidity, hospitalization, and mortality in these patients.

Pulmonary rehabilitation is the treatment used to increase exercise capacity and reduce overall symptoms and readmission of COPD. Pulmonary rehabilitation is directly associated with enhanced strength of the quadriceps femoris muscle group, indicating that increasing leg strength can benefit patients with COPD. The study conducted by the research team was a randomized, placebo-controlled, double-blind model that evaluated both the efficacy and tolerability of GSK2881078 in both men and postmenopausal women previously diagnosed with COPD. All patients were between the ages of 50 and 75 and COPD diagnosis was confirmed by a predicted postbronchodilator forced expiratory volume between 30% and 65% [3].

Additional criteria related to muscle weakness and impaired functioning included a score of 1-3 on the 5-repetition sit-to-stand component of the physical performance evaluation. Smoking status and a body mass index ranging from 18-32 kg/m^2 (BMI) of the patient were also taken into consideration; smoking history was defined as smoking a minimum of 10 packs per year. Patients were excluded from the trial if they were concurrently using oral steroids or within 4 weeks of the experimental period. The exclusion criteria also included instances of COPD exacerbation resulting in the use of oral steroids, hospitalization within 4 weeks of the experimental periods, a score of 0 on the physical performance evaluation, or any other conditions or medications that could potentially influence muscle mass or muscle function.

Prior to the beginning of treatment, all patients were randomly assigned to either the experimental group or the placebo group. Female participants were administered 1 mg of either a placebo or active GSK2881078 while male participants were administered 2 mg of either compound. All test subjects received oral doses of the compound over the course of the 13 week experimental period. Additionally, each participant followed a standardized home-exercise program delivered via smartphone app in order for each subject to accurately track their activity. The exercise program included a constituted daily step goal and strengthening exercises 3 to 4 times weekly [3].

All primary and secondary endpoints were assessed 9 days prior to the beginning of the treatment period, as well as on day 1 (baseline measurements), day 14, day 28, day 56, day 80 and day 90. A post-treatment follow-up appointment took place on day 132. While many of the endpoints being assessed in their study were related to the safety aspect of the SARM, the research team also made it a point to record any changes in leg strength measured by a one repetition maximum (1RM) on the leg press [3].

 

Discussion

1) The research team of Bhasin and Jasuja were able to achieve selectivity of SARMs by elucidating the mechanism of testosterone’s action on the prostate, as well as how molecules farther downstream were associated with activation of AR signaling in skeletal muscle. Analysis of muscle biopsies collected from male test subjects treated with varying doses of testestore revealed that administration of the compound led to hypertrophy in type I and type II muscle fibers. In relation to testosterone dosage, both type I and type II fibers experienced significant changes in cross-sectional areas. It is important to note that there was no change observed in the absolute number or the relative proportion of type I and type II fibers in response to testosterone administration [1].

Hypertrophy of the skeletal muscle was further examined through observation of muscle satellite cells and the myonuclear number. These variables were assessed through the use of electron microscopy, using direct counting and spatial orientation methods at baseline and after 20 weeks of GnRH agonist and testosterone enanthate treatment. Results reported that absolute and percent satellite cell number was significantly greater than baseline after 20 weeks of the test subjects receiving supraphysiologic doses of testosterone. The observed changes in the number of satellite cells correlated with changes in total and free testosterone levels, indicating that muscle fiber hypertrophy induced by testosterone is correlated with an increase in the number of satellite cells and the myonuclear number [1].

2) Results of the study conducted by Neil et. Al reported that administration of multiple doses of GSK2881078 led to significant increases in half-life, Cmax, and AUC parameters in both male and female subjects. The accumulation ratios of both male and female participants was calculated by dividing the drug concentration observed during the dosing interval at steady state by the drug concentration observed during the dosing interval directly following administration of the first dose of the SARM. The accumulation ratio for males on day 28 were found to range from 14- to 16-fold and from 14- to 23-fold for females. Additionally, the results displayed that 1 to 1.5 hours was the approximate median time at which the observed Cmax values remained consistent. A dose-dependent increase in half-life was observed in both male and female test subjects. When administered doses of 0.5, 1.5, and 0.75 mg of GSK2881078, female participants exhibited an increase in elimination half-life of 131, 190, and 200 hours, respectively. When administered doses of 1.0, 1.5, and 4.0 mg of GSK2881078, male participants exhibited an increase in elimination half-life of 145, 145, and 185 hours, respectively [2].

Figure 1: Changes in Cmax and AUC in both male and females in response to different doses of GSK2881078

In comparison to the participants administered a placebo treatment, those given the experimental compound experienced a significant increase in the accrual of lean mass. These findings were confirmed by MRI and DXA scans that highlight the dose-dependent changes in total lean body mass, appendicular body mass, and thigh mass volume. The test subjects involved in the second portion of the study experienced a secondary increase in lean mass after an additional 28 days of administration of GSK2881078 [2].

The research team observed that the female test subjects seemed to be more sensitive to treatment with the SARM in comparison to males, after 56 days of treatment there was an 1.83 kg and 1.21 kg increase in appendicular lean body mass, respectively. It is important to mention that in male test subjects there was no significant difference between the effects of dosing for 28 days versus 56 days. From day 28 to 56 there was no apparent change in appendicular lean body mass, only a slight increase in total lean body mass, and an increase in thigh muscle volume detected by MRI. All changes in lean mass gains were found to be represented consistently between DXA and MRI and were achieved in the absence of resistance training [2].

Figure 2: Mean changes in lean body mass from baseline in response to different treatment doses of GSK2881078

Overall, GSK2881078 was found to be well tolerated amongst all treatment groups for up to 56 days without the recurrence of any significant adverse side effects. In regards to liver functioning, the most noticeable alterations from baseline were shown in alanine aminotransferase and aspartate aminotransferase. Results also reported that alkaline phosphatase typically decreased after administration of the SARM while both total and direct bilirubin levels remained generally unchanged.

When examining the changes in lipids in each subject, the researchers noticed that administration of GSk2881078 resulted in a decrease in high-density lipoprotein (HDL) cholesterol. This result was seen in both male and female test subjects while the maximum level of reduction reached approximately 30%-45% from baseline. A similar reduction was shown in levels of apolipoprotein A1. All test subjects attended follow-up visits until there was a noticeable return to baseline either in apolipoprotein AI, HDL cholesterol, or LDL cholesterol. All hormone levels were monitored as well and reported that any reductions in total testosterone in male subjects after administration of the SARM, were all completely reversible. There were no observed changes in prostate-specific antigen in men and no significant changes in FSH, LH, estradiol, or progesterone in female subjects. However, in female subjects there was a reversible decrease in sex hormone-binding globulin [2].

3) In total, 96 participants, 47 females and 49 males, were randomly assigned to be included in the research experiment conducted by Mohan et. al. While 96 subjects were included at the beginning of the treatment period, by the end of the trial there were 39 females and 38 males. Overall, 2 females and 3 males of the experimental group and 5 males in the placebo group withdrew from the study due to reported instances of adverse events. The research team thought it was important to mention that there were no significant differences in baseline characteristics that were measured, including sex, ethnicity, BMI, and FEV1% prediction, in both males and females in the placebo and experimental groups. Additionally, more than 90% of the participants included in the study were compliant with their daily exercise routine [3].

Apart from the small number of participants that dropped out of the study due to adverse events, treatment with GSK2881078 was well tolerated by the participants of the experiment. Results of the study reported that both cohorts experienced reductions in fasting glucose and HDL-C were the primary metabolic changes elicited by supplementation with GSK2881078. There were no reported changes in hematocrit levels while a slight increase in platelet counts was observed. It was also mentioned that there were no significant differences between the experimental group and the placebo group in the recorded mean levels of prostate-specific antigen. Furthermore, treatment with GSK2881078 was found to increase leg strength by 7.0% from baseline in male test subjects and 5.2% from baseline in female test subjects. Expressed as a force in kg these percentages correlated to an 11.8 kg and 8.0 kg increase in leg strength, respectively. Changes in total lean body mass (LBM) and appendicular LBM were also recorded; while there was no relation between leg strength and LBM, there was a 2.1 kg increase from baseline in total LBM in both male and female test subjects following treatment with the SARM [3].

Figure 3: Changes in (A) muscle strength in females, (B) muscle strength in males, (C) LBM in females, and (D) LBM in males.

Following treatment with GSK2881078, total scores on the physical performance examination assessments increased by 0.2 in females, and 0.1 in males. Time spent on the 5-repetition sit-to-stand test there was a 1.0 second decrease in mean times for female test subjects and a 1.9 second decrease in mean times for male test subjects. Additionally, there were no significant differences measured in the scores of the 4-meter gait speed assessment, incremental shuttle walking test, or the endurance shuttle walking test. There were also no relevant changes from baseline in any of the respiratory measures examined by the research team. Treatment with the SARM was also linked to a slight increase in daily average steps in comparison with the placebo group. There was a 786 step increase from baseline in females treated with GSK2881078 and a 247 step decrease from baseline in females treated with the placebo. In males treated with the SARM there was a recorded 611.4 step increase from baseline and a 527.1 step decrease from baseline in males treated with the placebo [3].

Figure 4: Changes in daily step counts in (A) females and (B) males.

As it was previously mentioned, after the 90 day experimental treatment period all participants attended a follow-up visit on day 132. Following treatment with the SARM there was a 16.9% change from baseline in leg strength in female participants and 8.0% change from baseline in leg strength in male participants. There was also a 1.2 kg increase in LBM in female test subjects and an 0.8 kg increase in LBM in male test subjects. Based on these findings the research team was able to conclude that GSK2881078 is not only tolerable but also leads to increased LBM in individuals experiencing muscle weakness and symptoms of COPD [3].

 

Disclaimer

**LAB USE ONLY**
*This information is for educational purposes only and does not constitute medical advice. THE PRODUCTS DESCRIBED HEREIN ARE FOR RESEARCH USE ONLY. All clinical research must be conducted with oversight from the appropriate Institutional Review Board (IRB). All preclinical research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).

 

Citations

[1] Bhasin S, Jasuja R. Selective androgen receptor modulators as function promoting therapies. Curr Opin Clin Nutr Metab Care. 2009 May;12(3):232-40. doi: 10.1097/MCO.0b013e32832a3d79. PMID: 19357508; PMCID: PMC2907129.

[2] David Neil, Richard V Clark, Mindy Magee, Julia Billiard, Ann Chan, Zhengyu Xue, Alan Russell, GSK2881078, a SARM, Produces Dose-Dependent Increases in Lean Mass in Healthy Older Men and Women, The Journal of Clinical Endocrinology & Metabolism, Volume 103, Issue 9, September 2018, Pages 3215–3224, https://doi.org/10.1210/jc.2017-02644

[3] Mohan D, Rossiter H, Watz H, Fogarty C, Evans RA, Man W, Tabberer M, Beerahee M, Kumar S, Millns H, Thomas S, Tal-Singer R, Russell AJ, Holland MC, Akinseye C, Neil D, Polkey MI. Selective androgen receptor modulation for muscle weakness in chronic obstructive pulmonary disease: a randomised control trial. Thorax. 2023 Mar;78(3):258-266. doi: 10.1136/thorax-2021-218360. Epub 2022 Oct 25. PMID: 36283827; PMCID: PMC9985744.

 

Navigating The Potential Of Receptor Modulators Through GSK-2881087

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12-18-2023-Umbrella-Labs-GSK-2881078-Certificate-Of-Analysis-COA.pdf

 

 

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Additional information

Weight	4 oz
Dimensions	3 × 3 × 3 in
Formula Option	Poly-Cell Formula, Polyethylene Glycol (Original)
CAS Number‎	917891-35-1-1196133-39-7
Size	30 Millilitres (1oz), 60 Millilitres (2oz)
ChemSpider ID	35143239