LGD-4033

Last updated
LGD-4033
LGD-4033.svg
Clinical data
SynonymsVK5211; Ligandrol
Routes of
administration 		By mouth
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 24-36 hours [1]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C14H12F6N2O
Molar mass 338.253 g·mol−1
3D model (JSmol)

LGD-4033 (VK5211, Ligandrol) [2] is an investigational selective androgen receptor modulator (SARM) for treatment of conditions such as muscle wasting and osteoporosis, discovered by Ligand Pharmaceuticals and currently under development by Viking Therapeutics. [3] [4]

Selective androgen receptor modulator class of pharmaceutical drugs

Selective androgen receptor modulators or SARMs are a novel class of androgen receptor ligands.

Muscle contractile soft tissue of mammals

Muscle is a soft tissue found in most animals. Muscle cells contain protein filaments of actin and myosin that slide past one another, producing a contraction that changes both the length and the shape of the cell. Muscles function to produce force and motion. They are primarily responsible for maintaining and changing posture, locomotion, as well as movement of internal organs, such as the contraction of the heart and the movement of food through the digestive system via peristalsis.

Osteoporosis bone resorption disease characterized by decreased density of normally mineralized bone which results in the thinning of bone tissue and decreased mechanical strength

Osteoporosis is a disease in which bone weakening increases the risk of a broken bone. It is the most common reason for a broken bone among the elderly. Bones that commonly break include the vertebrae in the spine, the bones of the forearm, and the hip. Until a broken bone occurs there are typically no symptoms. Bones may weaken to such a degree that a break may occur with minor stress or spontaneously. Chronic pain and a decreased ability to carry out normal activities may occur following a broken bone.

Contents

Commercial environment

Viking Therapeutics does not currently manufacture any pharmaceutical products, but is developing several products to treat metabolic and endocrine disorders. Thus, the company relies upon investments from stockholders and business partners. The company completed its Initial Public Offering in the 2nd quarter of Fiscal Year 2015, generating $22.3M in net proceeds. [5] Viking Therapeutics assumed the largest expense in 2014 from cited Research and Development costs ($21.2M), which may be related to purchase of required equipment and facilities to develop the drug candidates licensed by Ligand Pharmaceuticals in that year, including LGD-4033. [5]

Financial risks of development

Viking Therapeutics is yet to bring a drug to market. If one or several of their drug candidates does not pass clinical trials before one is successfully brought to market, then a significant amount of stockholders would likely sell their stocks, seriously reducing revenue and capability to continue development of LGD-4033. Additionally, as noted in the Form 10-Q submitted on 10 November 2016, Viking currently relies heavily upon licensed technologies by Ligand Pharmaceutics. If Viking Therapeutics were to lose this license, then its operating capability would be severely impacted. [6]

Other commercial aspects

Ligand Pharmaceutics has disclosed that its royalty fee incurred upon Viking Therapeutics for production and sale of LGD-4033 would be 7.25-9.25% of the product revenue. [7]

Another promising drug candidate, VK2809, is expected to drive a major shift in the market cap of Viking Therapeutics and its share of the market for TRβ agonists, which is currently dominated by Madrigal Pharmaceuticals. [8] This would improve the company portfolio as a whole, and would allow for greater capitalization upon the potential success of LGD-4033.

Intellectual property

Ligand Pharmaceuticals has patents filed for the manufacture and therapeutic use of certain compounds occupying several stated chemical structures, which are intended for use as selective androgen receptor modulators. The patent is filed under the following designations: US8519158 B2, US8865918, US9359285, US20070254875, US20140005186, US20150099720, and WO2005090282A1. The patents will expire on March 12, 2025. These patents effectively protect any future capitalization upon LGD-4033 in the market by Viking and Ligand through their licensing agreement. [9]

Regulatory information

LGD-4033 is currently an Investigational New Drug.

Pre-clinical

Oral administration of the drug to cynomolgus monkeys at daily doses varying from 0 to 75 mg/kg over 13 weeks demonstrated significant body weight gain in both males and females. After 48 days, the 75 mg/kg dose testing was halted due to toxicity concerns, but this did not negatively impact development as the dose is significantly higher than those being utilized in the Phase 2 clinical trial. [10]

Clinical trials

In a Phase 1 clinical trial of 76 adult male humans in which the dose size was varied, a dose-dependent increase in lean body mass was observed with no significant adverse events over 21 days. [2]

The Phase 2 clinical trial, initiated on 3 November 2016, consists of 120 patients recovering from hip fracture surgery. The randomized study participants will receive either a placebo or varying dose sizes of LGD-4033 over a period of 12 weeks, with improved lean body mass as the primary endpoint. Other endpoints include satisfactory results in terms of quality of life, safety, and pharmacokinetics. [11]

Illicit use

Though not an approved drug, LGD-4033 has been sold on the black market. [12] [13]

LGD-4033 is currently on the World Anti-Doping Association list of prohibited drugs [14] and has been found in drug testing samples of some athletes. [15] In 2015, the quarterback of the Florida Gators, Will Grier, was suspended for testing positive for LGD-4033, a claim that the University of Florida denies. [16] In 2017, Joakim Noah was banned for twenty games by the NBA for testing positive for LGD-4033. [17] In 2019, Australian swimmer Shayna Jack tested positive for LGD-4033. She denies knowingly taking the substance. [18]

Related Research Articles

Bicalutamide chemical compound

Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical removal of the testicles to treat advanced prostate cancer. Bicalutamide may also be used to treat excessive hair growth in women, as a component of feminizing hormone therapy for transgender women, to treat early puberty in boys, and to prevent overly long-lasting erections in men. It is taken by mouth.

Lasofoxifene chemical compound

Lasofoxifene, sold under the brand name Fablyn, is a nonsteroidal selective estrogen receptor modulator (SERM) which is marketed by Pfizer in Lithuania and Portugal for the prevention and treatment of osteoporosis and for the treatment of vaginal atrophy, and the result of an exclusive research collaboration with Ligand Pharmaceuticals (LGND). It also appears to have had a statistically significant effect of reducing breast cancer in women according to a study published in The Journal of the National Cancer Institute.

Olmesartan/amlodipine, sold under the brand name Azor, among others is a combination medication used to treat high blood pressure. It combines two antihypertensive agents in a film-coated tablet. It contains amlodipine, a calcium channel blocker, and olmesartan medoxomil, an angiotensin-2 receptor antagonist. The patent is held by Daiichi Sankyo Pharmaceuticals. Daiichi Sankyo filed a supplemental New Drug Application (sNDA) for Azor with the United States Food and Drug Administration on September 17, 2008. Azor has been studied in clinical trials; one test showed it reduced blood pressure during a 24-hour period and was well tolerated.

Enzalutamide chemical compound

Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is indicated for use in conjunction with castration in the treatment of metastatic castration-resistant prostate cancer (mCRPC) and nonmetastatic castration-resistant prostate cancer. It is taken by mouth.

BMS-564,929 chemical compound

BMS-564,929 is an investigational selective androgen receptor modulator (SARM) which is being developed by Bristol-Myers Squibb for treatment of the symptoms of age-related decline in androgen levels in men ("andropause"). These symptoms may include depression, loss of muscle mass and strength, reduction in libido and osteoporosis. Treatment with exogenous testosterone is effective in counteracting these symptoms but is associated with a range of side effects, the most serious of which is enlargement of the prostate gland, which can lead to benign prostatic hypertrophy and even prostate cancer. This means there is a clinical need for selective androgen receptor modulators, which produce anabolic effects in some tissues such as muscle and bone, but without stimulating androgen receptors in the prostate.

S-40503 chemical compound

S-40503 is an investigational selective androgen receptor modulator (SARM) developed by the Japanese company Kaken Pharmaceuticals, which was developed for the treatment of osteoporosis. SARMs are a new class of drugs which produce tissue-specific anabolic effects in some tissues such as muscle and bone, but without stimulating androgen receptors in other tissues such as in the prostate gland, thus avoiding side effects such as benign prostatic hypertrophy which can occur following treatment with unselective androgens like testosterone or anabolic steroids.

LGD-2226 chemical compound

LGD-2226 is an investigational selective androgen receptor modulator (SARM), which is being developed for treatment of muscle wasting and osteoporosis.

Enobosarm chemical compound

Enobosarm, also known as ostarine, is an investigational selective androgen receptor modulator (SARM) developed by GTx, Inc. for the treatment of conditions such as muscle wasting and osteoporosis, formerly under development by Merck & Company.

Andarine chemical compound

Andarine is an investigational selective androgen receptor modulator (SARM) developed by GTX, Inc for treatment of conditions such as muscle wasting, osteoporosis and benign prostatic hypertrophy, using the nonsteroidal antiandrogen bicalutamide as a lead compound.

LGD-3303 chemical compound

LGD-3303 is a drug which acts as a selective androgen receptor modulator (SARM), with good oral bioavailability. It is a selective agonist for the androgen receptor, producing functional selectivity with effective dissociation of anabolic and androgenic effects, acting as a partial agonist for androgenic effects, but a full agonist for anabolic effects. It has been investigated as a possible treatment for osteoporosis, and was shown in animal studies to enhance the effectiveness of a bisphosphonate drug.

GTx, Inc is a pharmaceutical company that is working on drugs in the selective estrogen receptor modulator (SERM) and selective androgen receptor modulator (SARM) classes. Its drugs in development include enobosarm (ostarine) and GTx-758.

Basimglurant chemical compound

Basimglurant (INN) is a negative allosteric modulator of the mGlu5 receptor which is under development by Roche and Chugai Pharmaceutical for the treatment of treatment-resistant depression and fragile X syndrome. As of November 2016, it has undergone phase II clinical trials for both of these indications.

TIK-301 chemical compound

TIK-301 (LY-156735) is an agonist for the melatonin receptors MT1 and MT2 that is under development for the treatment of insomnia and other sleep disorders. Its agonist action on MT1 and MT2 receptors in the suprachiasmatic nucleus in the brain enables its action as a chronobiotic. It is in the same class of melatonin receptor agonists as ramelteon and tasimelteon.

Ligand Pharmaceuticals is a biopharmaceutical company located in San Diego, California. Founded in 1987 as Progenx Inc., the company went public in 1992. Initially focused on developing its own drugs, a period of turbulence in the early 2000s culminated in its CEO being ejected by the shareholders and provoked a change in focus to the acquisition of existing drugs and forming partnerships to develop them further.

RAD140 chemical compound

RAD140 is an investigational selective androgen receptor modulator (SARM) for the treatment of conditions such as muscle wasting and breast cancer, currently under development by Radius Health, Inc. (RDUS).

Acetothiolutamide chemical compound

Acetothiolutamide is a selective androgen receptor modulator (SARM) derived from the nonsteroidal antiandrogen bicalutamide that was described in 2002 and was one of the first SARMs to be discovered and developed. It is a high-affinity, selective ligand of the androgen receptor (AR), where it acts as a full agonist in vitro, and has in vitro potency comparable to that of testosterone. However, in vivo, acetothiolutamide displayed overall negligible androgenic effects, though significant anabolic effects were observed at high doses. In addition, notable antiandrogen effects were observed in castrated male rats treated with testosterone propionate. The discrepancy between the in vitro and in vivo actions of acetothiolutamide was determined to be related to rapid plasma clearance and extensive hepatic metabolism into a variety of metabolites with differing pharmacological activity, including AR partial agonism and antagonism. In accordance with its poor metabolic stability, acetothiolutamide is not orally bioavailable, and shows activity only via injected routes such as subcutaneous and intravenous.

LG121071 chemical compound

LG121071 is a selective androgen receptor modulator (SARM) developed by Ligand Pharmaceuticals that was first described in 1999 and was the first orally active nonsteroidal androgen to be discovered. It is a tricyclic quinolone derivative, structurally distinct from other nonsteroidal AR agonists like andarine and enobosarm (ostarine). The drug acts as a high-affinity full agonist of the androgen receptor (AR), with a potency and efficacy that is said to be equivalent to that of dihydrotestosterone (DHT). Unlike testosterone, but similarly to DHT, LG121071 and other nonsteroidal androgens cannot be potentiated by 5α-reductase in androgenic tissues, and for this reason, show tissue-selective androgenic effects. In accordance, they are said to possess full anabolic activity with reduced androgenic activity, similarly to anabolic-androgenic steroids.

LG-120907

LG-120907 is a nonsteroidal antiandrogen (NSAA) of the quinoline group which was developed by Ligand Pharmaceuticals along with selective androgen receptor modulators (SARMs) like LG-121071 and was never marketed. The drug is a high-affinity antagonist of the androgen receptor (AR) with a Ki value of 26 nM and has been found to inhibit growth of the ventral prostate and seminal vesicles in male rats without increasing circulating levels of luteinizing hormone or testosterone. However, this tissue selectivity has not been assessed in humans. LG-120907 is orally active and shows greater oral potency than the arylpropionamide NSAA flutamide.

RU-59063 chemical compound

RU-59063 is a nonsteroidal androgen or selective androgen receptor modulator (SARM) which was first described in 1994 and was never marketed. It was originally thought to be a potent antiandrogen, but subsequent research found that it actually possesses dose-dependent androgenic activity, albeit with lower efficacy than dihydrotestosterone (DHT). The drug is an N-substituted arylthiohydantoin and was derived from the first-generation nonsteroidal antiandrogen (NSAA) nilutamide. The second-generation NSAAs enzalutamide, RD-162, and apalutamide were derived from RU-59063.

References

  1. ↑ Basaria S, Collins L, Dillon EL, Orwoll K, Storer TW, et al. (Jan 2013). "The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men". J Gerontol A Biol Sci Med Sci. 68 (1): 87–95. doi:10.1093/gerona/gls078. PMC   4111291 . PMID   22459616.
  2. 1 2 Basaria, S., L. Collins, E. L. Dillon, K. Orwoll, T. W. Storer, R. Miciek, J. Ulloor, A. Zhang, R. Eder, H. Zientek, G. Gordon, S. Kazmi, M. Sheffield-Moore, and S. Bhasin. "The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men." The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 68.1 (2012): 87-95. Web. 21 Nov. 2016.
  3. ↑ "Ligand Presents New Preclinical Data on its Lead SARM Molecule LGD-4033 at the Gerontological Society of America Annual Meeting" (Press release). San Diego: Ligand Pharmaceuticals. November 20, 2009. Retrieved November 23, 2014.
  4. ↑ Viking Signs Broad Licensing Deal With Ligand Pharmaceuticals for Rights to Five Novel Therapeutic Programs
  5. 1 2 Lian, Brian, Ph.D. "Q2 2015." Viking Therapeutics InvestorRoom. Viking Therapeutics, Inc., 3 Aug. 2015. Web. 21 Nov. 2016.
  6. ↑ Lian, Brian, Ph.D. “Form 10-Q: Viking Therapeutics, Inc. –VKTX.” www.vikingtherapeutics.com (2016).Web. 21 November 2016.
  7. ↑ "Royalty Table :: Ligand Pharmaceuticals, Inc. (LGND)." Royalty Table :: Ligand Pharmaceuticals, Inc. (LGND). Ligand Pharmaceuticals, Inc., 21 Nov. 2016. Web. 21 Nov. 2016.
  8. ↑ Bautz, David, PhD. "VKTX: Phase 2 Study of VK5211 for Hip Fracture Ongoing; Phase 2 Study of VK2809 for Hypercholersterolemia to Commence in Mid-2016." Yahoo Finance - Business Finance, Stock Market, Quotes, News. Yahoo, Inc., 16 May 2016. Web. 21 Nov. 2016.
  9. ↑ Zhi, Lin, Robert I. Higuchi, Cornelis Arjan Van Oeveren, Thomas Lot Stevens Lau, and Ligand Pharmaceuticals Incorporated. Androgen Receptor Modulator Compounds and Methods. Ligand Pharmaceuticals Incorporated, assignee. Patent US 8519158 B2. 11 Mar. 2005. Print.
  10. ↑ Bautz, David, PhD. "VKTX: Additional Preclinical Data Shows Robust and Durable Weight Gain for VK5211-Treated Primates." Yahoo. Yahoo, Inc., 8 Dec. 2015. Web. 21 Nov. 2016.
  11. ↑ "Viking Therapeutics Initiates Phase 2 Trial of VK5211 in Patients Recovering From Hip Fracture." FierceBiotech. Questex LLC, 03 Nov. 2015. Web. 21 Nov. 2016.
  12. ↑ Geldof, Lore; Pozo, Oscar J.; Lootens, Leen; Morthier, Wouter; Van Eenoo, Peter; Deventer, Koen (2017). "In vitro metabolism study of a black market product containing SARM LGD-4033". Drug Testing and Analysis. 9 (2): 168–178. doi:10.1002/dta.1930. PMID   26767942.
  13. ↑ Krug, Oliver; Thomas, Andreas; Walpurgis, Katja; Piper, Thomas; Sigmund, Gerd; Schänzer, Wilhelm; Laussmann, Tim; Thevis, Mario (2014). "Identification of black market products and potential doping agents in Germany 2010–2013". European Journal of Clinical Pharmacology. 70 (11): 1303–1311. doi:10.1007/s00228-014-1743-5. PMID   25168622.
  14. ↑ "Prohibited List".
  15. ↑ Cox, Holly D.; Eichner, Daniel (2017). "Detection of LGD-4033 and its metabolites in athlete urine samples". Drug Testing and Analysis. 9 (1): 127–134. doi:10.1002/dta.1986. PMID   27168428.
  16. ↑ Trahan, Kevin (12 October 2015). "Florida starting QB Will Grier suspended for at least 2015 after taking banned substance". SB Nation. Retrieved 20 October 2015.
  17. ↑ "NBA bans Joakim Noah 20 games for drug violation". Fox Sports. March 25, 2017.
  18. ↑ James Maasdorp (July 28, 2019). "Shayna Jack reveals banned substance Ligandrol was behind her doping suspension from swimming". Australian Broadcasting Corporation . Retrieved July 28, 2019.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.