Description

GSK-2881078 SARMs Gel

 

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	Store in cool dry environment, away from direct sunlight.
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 regarding the efficacy of GSK2881078 has highlighted the compound’s potential to improve mobility, functional activity, and muscle weakness in cases 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) 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.

3) GSK2881078 was found to be successful in increased lower extremity limb strength in both male and female individuals diagnosed with 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 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 [2].

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 [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.

 

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) 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 [2].

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 [2].

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 [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 5: 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 6: 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] 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.

[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

 

 

 

 

File Name	View/Download
12-18-2023-Umbrella-Labs-GSK-2881078-Certificate-Of-Analysis-COA.pdf

 

 

VIEW CERTIFICATES OF ANALYSIS (COA)

 

 

Additional information

Weight	4 oz
Dimensions	3 × 3 × 3 in
Packs	Packs of 5, Packs of 10, Packs of 30