LG121071

Last updated
LG121071
LG-121071.svg
Clinical data
Other namesLG-121071; LGD-121071
Identifiers
  • 6-Ethyl-4-(trifluoromethyl)-1H,2H,6H,7H,8H,9H-pyrido[3,2-g]quinolin-2-one
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C15H15F3N2O
Molar mass 296.293 g·mol−1
3D model (JSmol)
  • CCC1CCNC2=C1C=C3C(=CC(=O)NC3=C2)C(F)(F)F
  • InChI=1S/C15H15F3N2O/c1-2-8-3-4-19-12-7-13-10(5-9(8)12)11(15(16,17)18)6-14(21)20-13/h5-8,19H,2-4H2,1H3,(H,20,21)
  • Key:SZPPQFARTYXRKU-UHFFFAOYSA-N

LG121071 (or LGD-121071) 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. [1] [2] It is a tricyclic quinolone derivative, structurally distinct from other nonsteroidal AR agonists like andarine and enobosarm (ostarine). [2] The drug acts as a high-affinity full agonist of the androgen receptor (AR) (Ki = 17 nM), [2] with a potency and efficacy that is said to be equivalent to that of dihydrotestosterone (DHT). [3] Unlike testosterone, but similarly to DHT, LG121071 and other nonsteroidal androgens cannot be potentiated by 5α-reductase in androgenic tissues (nor aromatized into estrogenic metabolites), and for this reason, show tissue-selective androgenic effects. [4] In accordance, they are said to possess full anabolic activity with reduced androgenic activity, similarly to anabolic-androgenic steroids. [5]

The in vitro metabolism of LG121071 has been characterized in anticipation of its possible use as a doping agent. [5] [6]

See also

Related Research Articles

<span class="mw-page-title-main">Selective androgen receptor modulator</span> Class of pharmaceutical drugs

Selective androgen receptor modulators (SARMs) are a class of drugs that selectively activate the androgen receptor in specific tissues, promoting muscle and bone growth while having less effect on male reproductive tissues like the prostate gland.

<span class="mw-page-title-main">Anabolic steroid</span> Class of drugs

Anabolic steroids, also known as anabolic-androgenic steroids (AAS), are a class of drugs that are structurally related to testosterone, the main male sex hormone, and produce effects by binding to the androgen receptor (AR). Anabolic steroids have a number of medical uses, but are also used by athletes to increase muscle size, strength, and performance.

<span class="mw-page-title-main">BMS-564,929</span> 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 hyperplasia 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.

<span class="mw-page-title-main">S-40503</span> 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 that 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 hyperplasia which can occur following treatment with unselective androgens like testosterone or anabolic steroids.

<span class="mw-page-title-main">LGD-2226</span> Chemical compound

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

<span class="mw-page-title-main">Enobosarm</span> Investigational selective androgen receptor modulator

Enobosarm, also formerly known as ostarine and by the developmental code names GTx-024, MK-2866, and S-22, is a selective androgen receptor modulator (SARM) which is under development for the treatment of androgen receptor-positive breast cancer in women and for improvement of body composition in people taking GLP-1 receptor agonists like semaglutide. It was also under development for a variety of other indications, including treatment of cachexia, Duchenne muscular dystrophy, muscle atrophy or sarcopenia, and stress urinary incontinence, but development for all other uses has been discontinued. Enobosarm was evaluated for the treatment of muscle wasting related to cancer in late-stage clinical trials, and the drug improved lean body mass in these trials, but it was not effective in improving muscle strength. As a result, enobosarm was not approved and development for this use was terminated. Enobosarm is taken by mouth.

<span class="mw-page-title-main">Andarine</span> Chemical compound

Andarine is a selective androgen receptor modulator (SARM) which was developed by GTX, Inc for the treatment of conditions such as muscle wasting, osteoporosis, and benign prostatic hyperplasia (BPH), using the nonsteroidal antiandrogen bicalutamide as a lead compound. Development of andarine for all indications has been discontinued, in favor of the structurally related and improved compound enobosarm.

<span class="mw-page-title-main">Bolandione</span> Chemical compound

Bolandione, also known as 19-norandrostenedione, as well as 19-norandrost-4-en-3,17-dione or estr-4-ene-3,17-dione, is a precursor of the anabolic-androgenic steroid (AAS) nandrolone (19-nortestosterone). Until 2005, bolandione was available without prescription in United States, where it was marketed as a prohormone, but it is now classified as a Schedule III drug. It is also banned from use in many sports, including the Olympic Games, under the World Anti-Doping Code. Bolandione is readily metabolized to nandrolone after oral administration, but its potency to transactivate the androgen receptor dependent reporter gene expression is 10 times lower as compared to dihydrotestosterone (DHT).

<span class="mw-page-title-main">AC-262,536</span> Chemical compound

AC-262536 is a drug developed by Acadia Pharmaceuticals which acts as a selective androgen receptor modulator (SARM). Chemically it possesses endo-exo isomerism, with the endo form being the active form. It acts as a partial agonist for the androgen receptor with a Ki of 5 nM, and no significant affinity for any other receptors tested. In animal studies it produced a maximal effect of around 66% of the levator ani muscle weight increase of testosterone, but only around 27% of its maximal effect on prostate gland weight. It is an aniline SARM related to ACP-105 and vosilasarm (RAD140).

<span class="mw-page-title-main">LGD-3303</span> 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.

The first antiandrogen was discovered in the 1960s. Antiandrogens antagonise the androgen receptor (AR) and thereby block the biological effects of testosterone and dihydrotestosterone (DHT). Antiandrogens are important for men with hormonally responsive diseases like prostate cancer, benign prostatic hyperplasia (BHP), acne, seborrhea, hirsutism and androgen alopecia. Antiandrogens are mainly used for the treatment of prostate diseases. Research from 2010 suggests that ARs could be linked to the disease progression of triple-negative breast cancer and salivary duct carcinoma and that antiandrogens can potentially be used to treat it.

<span class="mw-page-title-main">Ligandrol</span> Chemical compound

LGD-4033, also known by the developmental code name VK5211 and by the black-market name Ligandrol, is a selective androgen receptor modulator (SARM) which is under development for the treatment of muscle atrophy in people with hip fracture. It was also under development for the treatment of cachexia, hypogonadism, and osteoporosis, but development for these indications was discontinued. LGD-4033 has been reported to dose-dependently improve lean body mass and muscle strength in preliminary clinical trials, but is still being developed and has not been approved for medical use. The drug is taken by mouth.

<span class="mw-page-title-main">Vosilasarm</span> Chemical compound

Vosilasarm, also known by the development codes RAD140 and EP0062 and by the black-market name Testolone or Testalone, is a selective androgen receptor modulator (SARM) which is under development for the treatment of hormone-sensitive breast cancer. It is specifically under development for the treatment of androgen receptor-positive, estrogen receptor-negative, HER2-negative advanced breast cancer. Vosilasarm was also previously under development for the treatment of sarcopenia, osteoporosis, and weight loss due to cancer cachexia, but development for these indications was discontinued. The drug is taken by mouth.

<span class="mw-page-title-main">Acetothiolutamide</span> 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.

<span class="mw-page-title-main">TFM-4AS-1</span> Abandoned drug

TFM-4AS-1 is a dual selective androgen receptor modulator (SARM) and 5α-reductase inhibitor. It is a potent and selective partial agonist (Emax = 55%) of the androgen receptor (IC50 = 30 nM) and inhibitor of 5α-reductase types I and II (IC50 = 2 and 3 nM, respectively). TFM-4AS-1 shows tissue-selective androgenic effects; it promotes the accumulation of bone and muscle mass and has reduced effects in reproductive tissues and sebaceous glands. In an animal study, TFM-4AS-1 stimulated sebaceous gland formation only 31% as much as dihydrotestosterone (DHT) at doses that were as anabolic or more so than DHT. In addition, TFM-4AS-1 only weakly promoted growth of the prostate gland and it partially antagonized the actions of DHT in the seminal vesicles and endogenous androgens in the prostate gland. Structurally, TFM-4AS-1 is a 4-azasteroid. A structurally related and more advanced version of TFM-4AS-1, MK-0773, was developed and pursued for potential pharmaceutical use.

<span class="mw-page-title-main">MK-0773</span> Abandoned drug

MK-0773, also known as PF-05314882, is a steroidal, orally active selective androgen receptor modulator (SARM) that was under development by Merck and GTx for the treatment of sarcopenia in women and men. Clinical trials for sarcopenia began in late 2007 but the collaboration between Merck and GTx ended in early 2010 and GTx terminated development of MK-0773 shortly thereafter. MK-0773 was developed as a more advanced version of the related compound TFM-4AS-1.

<span class="mw-page-title-main">LG-120907</span> Nonsteroidal antiandrogen of the quinoline group

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.

<span class="mw-page-title-main">RU-59063</span> 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.

<span class="mw-page-title-main">JNJ-26146900</span> Abandoned prostate cancer drug

JNJ-26146900 is a selective androgen receptor modulator (SARM) which was developed by Johnson & Johnson for the potential treatment of prostate cancer but was never marketed.

References

  1. Hamann LG, Mani NS, Davis RL, Wang XN, Marschke KB, Jones TK (January 1999). "Discovery of a potent, orally active, nonsteroidal androgen receptor agonist: 4-ethyl-1,2,3,4-tetrahydro-6- (trifluoromethyl)-8-pyridono[5,6-g]- quinoline (LG121071)". Journal of Medicinal Chemistry. 42 (2): 210–212. doi:10.1021/jm9806648. PMID   9925725.
  2. 1 2 3 Gao W, Kim J, Dalton JT (August 2006). "Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor ligands". Pharmaceutical Research. 23 (8): 1641–1658. doi:10.1007/s11095-006-9024-3. PMC   2072875 . PMID   16841196.
  3. Chengalvala M, Oh T, Roy AK (2005). "Selective androgen receptor modulators". Expert Opinion on Therapeutic Patents. 13 (1): 59–66. doi:10.1517/13543776.13.1.59. ISSN   1354-3776. S2CID   219188263.
  4. Elbers JM, Grootenhuis AJ (April 2003). "New tissue-selective androgens: perspectives in the treatment of androgen deficits". Annales d'Endocrinologie. 64 (2): 183–188. PMID   12773961.
  5. 1 2 Knoop A, Krug O, Vincenti M, Schänzer W, Thevis M (2015). "In vitro metabolism studies on the selective androgen receptor modulator (SARM) LG121071 and its implementation into human doping controls using liquid chromatography-mass spectrometry". European Journal of Mass Spectrometry. 21 (1): 27–36. doi:10.1255/ejms.1328. PMID   25906032. S2CID   29918434.
  6. Gerace E, Salomone A, Fasano F, Costa R, Boschi D, Di Stilo A, Vincenti M (April 2011). "Validation of a GC/MS method for the detection of two quinolinone-derived selective androgen receptor modulators in doping control analysis". Analytical and Bioanalytical Chemistry. 400 (1): 137–144. doi:10.1007/s00216-010-4569-8. hdl: 2318/86557 . PMID   21165606. S2CID   43268790.