Description

GSK-2881078 SARM Liquid

 

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). The compound is currently being assessed for its ability 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) Pharmacokinetic analysis emphasized a dose-dependent increase in the half-life of GSK2881078, as well as a decrease in high-density lipoprotein and sex hormone-binding globulin.

 

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.

3) The research team of Clark et. Al evaluated the safety and tolerability as well as the pharmacokinetics and pharmacodynamics effects of GSK2881078 in healthy male subjects and healthy, postmenopausal female subjects. The study was split into part A and part B. Part A was defined as a four-way crossover design where each male subject only received a single, weekly dose of the SARM or a placebo compound over the course of 4 weeks. The first dose administered was 0.1 mg, the second was 0.2 mg, the third was 0 mg, and the fourth was 0.05 mg. The purpose of administering a 0 mg dose was to evaluate changes from baseline in GSK2881078 concentrations after receiving a dose of the compound during the previous dosing period.

Part B of the experiment included repeat administration of 0.05 mg doses of either a placebo or GSK2881078 over the course of 7 or 14 days. While both male and female subjects were included in this portion of the study, the research team used data from Part A in order to consider the half-life of the compound and approximate a twice daily loading regimen in order to maintain steady-state exposures over the 14 day experimental treatment period. Following the dosing period the test subjects underwent both safety and pharmacokinetic assessments. All participants of the experiment received standard meals prior to dose and were expected to remain at the testing facility throughout the duration of the study. Follow-up visits were scheduled for each subject with the last one occurring at day 42 post-dosing [3].

In order to assess safety and tolerability of the SARM, the researchers monitored results of clinical laboratory tests, ECGs, vitals, physical examinations, cardiac biomarkers, and any adverse events. In order to assess the pharmacokinetics of GSK2881078 plasma samples were collected from each subject and assayed through the use of a validated analytical method. This was followed by high-performance liquid chromatography/mass spectrometry analysis. Plasma concentration of the SARM was calculated based on calibration plots that display the typical concentrations of GSK2881078 in human plasma samples. Liquid-liquid extraction was used to analyze the concentrations of GSk28810978 in urine samples collected from the test subjects. This procedure was followed by ultra-high-performance liquid chromatography/mass spectrometry analysis.

To examine cardiac biomarkers and changes in hormone levels, fasting blood samples were obtained from each participant in both part A and part B. In part B blood samples were obtained at predose baseline and during the treatment period in order to detect levels of luteinizing hormone (LH), SHBG, follicle-stimulating hormone (FSH), prolactin, estradiol, progesterone, testosterone, and dihydrotestosterone (DHT). The blood samples collected also evaluated levels of total cholesterol, low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), high-density lipoprotein (HDL), triglycerides, and apolipoproteins A1 and B (apoA1 and ApoB). The blood samples gathered in both parts A and B were analyzed to assess levels of cardiac biomarkers, brain natriuretic peptide (BNP) and troponin. However, the samples from part B were used to examine levels of adrenocorticotropic hormone (ACTH), cortisol, dehydroepiandrosterone sulfate, insulin-like growth-factor-1, insulin-like growth factor-binding protein 3, T4, thyroid-stimulating hormone (TSH), and plasma levels of fasting insulin and glucose [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.

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) The results of the pharmacokinetic evaluation found that plasma concentrations of GSK2881078 initially entered a rapid absorption phase after both single administration of the SARM and repeated administration of the SARM. Part A of the study reported that the maximal observed concentration (Cmax) of plasma levels of GSK2881078 exhibited a dose-dependent increase while the time to maximal concentration (t-max) was comparable across all treatment groups. Additionally, the half-life of the compound was found to be greater than 100 hours in all treatment groups. Part B of the study reported that the time to maximal contraction was similar across treatment groups and days. The researchers also mentioned that there were no observed differences between male and female test subjects in the pharmacokinetic parameters measured. It is important to mention that plasma samples were obtained after the last dose of GSK2991078 was administered in order to record the time of the last measurable concentration. The measurements obtained were not consistent, ranging from 48 hours to 822 hours in males and 671 hours to 746 hours in females [3].

Figure 3: (A) Changes in plasma concentrations of GSK2881078 over a 24 hour period. (B) Changes in plasma concentrations of GSK2881078 over a 14 day treatment period

Reproductive hormones in both male and female test subjects were monitored and analyzed throughout the study. Administration of the SARM resulted in a reduction in levels of testosterone, DHT, and SHBGin male subjects. Levels of FSH also decreased in response to administration of varying doses, however, there was no observable pattern between the changes. Additionally, there was no apparent effect of administration of GSK2881078 on free testosterone and there were no consistent reductions in levels of LH in response to treatment with the SARM. Female test subjects experienced a dose-dependent reduction in levels of SHBG. As it was recorded by the research team of Clark et. Al, there were no other observable differences in the levels of other reproductive hormones in female test subjects [3].

Figure 4: Changes in the levels of SHBG in male and female subjects in response to treatment with GSK2881078

Male test subjects did not exhibit a noticeably consistent effect on the adrenal biomarkers in response to treatment with the SARM, while female subjects did not experience any clinically meaningful changes in levels of adrenal hormones in response to treatment with the SARM. Any changes recorded in adrenal and metabolic biomarkers were deemed clinically insignificant by the researchers. There were also no changes in levels of the cardiac biomarker BNP in both male and female subjects. Troponin levels were also shown to be within normal range while all ECG results were considered unremarkable [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] Clark RV, Walker AC, Andrews S, Turnbull P, Wald JA, Magee MH. Safety, pharmacokinetics and pharmacological effects of the selective androgen receptor modulator, GSK2881078, in healthy men and postmenopausal women. Br J Clin Pharmacol. 2017 Oct;83(10):2179-2194. doi: 10.1111/bcp.13316. Epub 2017 Jun 10. PMID: 28449232; PMCID: PMC5595940.

GSK-2881078 SARM is sold for laboratory research use only. Terms of sale apply. Not for human consumption, nor medical, veterinary, or household uses. Please familiarize yourself with our Terms & Conditions prior to ordering.

 

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