Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the androgen receptor (AR) and/or inhibiting or suppressing androgen production. They can be thought of as the functional opposites of AR agonists, for instance androgens and anabolic steroids (AAS) like testosterone, DHT, and nandrolone and selective androgen receptor modulators (SARMs) like enobosarm. Antiandrogens are one of three types of sex hormone antagonists, the others being antiestrogens and antiprogestogens.
Telapristone, as telapristone acetate, is a synthetic, steroidal selective progesterone receptor modulator (SPRM) related to mifepristone which is under development by Repros Therapeutics for the treatment of breast cancer, endometriosis, and uterine fibroids. It was originally developed by the National Institutes of Health (NIH), and, as of 2017, is in phase II clinical trials for the aforementioned indications. In addition to its activity as an SPRM, the drug also has some antiglucocorticoid activity.
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.
Eltoprazine is a serotonergic drug of the phenylpiperazine class which is described as a serenic or antiaggressive agent. It acts as an agonist of the serotonin 5-HT1A and 5-HT1B receptors and as an antagonist of the serotonin 5-HT2C receptor. The drug is closely related to fluprazine and batoprazine, which are similarly acting agents, and is also a known chemical precursor to S-15535 and lecozotan. Eltoprazine is or was under development for the treatment of aggression, attention deficit hyperactivity disorder (ADHD), cognition disorders, and drug-induced dyskinesia, but no recent development has been reported for these indications as of February 2022. It was also under development for the treatment of psychotic disorders, but development for this indication was discontinued. Eltoprazine was originated by Solvay and was developed by Elto Pharma, PsychoGenics, and Solvay.
A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens like testosterone and dihydrotestosterone (DHT). NSAAs are used in the treatment of androgen-dependent conditions in men and women. They are the converse of steroidal antiandrogens (SAAs), which are antiandrogens that are steroids and are structurally related to testosterone.
Seviteronel is an experimental cancer medication which is under development by Viamet Pharmaceuticals and Innocrin Pharmaceuticals for the treatment of prostate cancer and breast cancer. It is a nonsteroidal CYP17A1 inhibitor and works by inhibiting the production of androgens and estrogens in the body. As of July 2017, seviteronel is in phase II clinical trials for both prostate cancer and breast cancer. In January 2016, it was designated fast-track status by the United States Food and Drug Administration for prostate cancer. In April 2017, seviteronel received fast-track designation for breast cancer as well.
Roluperidone (former developmental code names MIN-101, CYR-101, MT-210) is a 5-HT2A and σ2 receptor antagonist under development by Minerva Neurosciences for the treatment of schizophrenia. One of its metabolites also has some affinity for the H1 receptor. Pre-clinical findings provide evidence of the effect of roluperidone on Brain-Derived Neurotrophic Factor (“BDNF”), which has been associated with neurogenesis, neuroplasticity, neuroprotection, synapse regulation, learning and memory.
Erteberel is a synthetic, nonsteroidal estrogen which acts as a selective ERβ agonist and was under development by Eli Lilly for the treatment of schizophrenia. It was specifically under investigation for the treatment of negative symptoms and cognitive impairment associated with the condition. It managed to reach phase II clinical trials for this indication in the United States in 2015. As of 2021 development has been discontinued. Erteberel was also under investigation for the treatment of benign prostatic hyperplasia and reached phase II clinical studies for this use but failed to improve symptoms in men with the condition and development for this indication was discontinued. The drug has also been proposed as a potential novel treatment for glioblastoma.
SERBA-2, short for selective estrogen receptor beta agonist-2, is a synthetic, nonsteroidal estrogen which acts as a selective ERβ agonist. For the ERα and ERβ, SERBA-2 has affinities (Ki) of 14.5 nM and 1.54 nM, efficacies of 85% and 100%, and EC50 values of 85 nM and 3.61 nM, respectively, demonstrating 9-fold binding selectivity and 11-fold functional selectivity for the ERβ over the ERα. An enantiomer of SERBA-2, erteberel (SERBA-1), is more potent and selective in comparison and is under development for the treatment of schizophrenia.
Vilaprisan is a synthetic and steroidal selective progesterone receptor modulator (SPRM) which is under development by Bayer HealthCare Pharmaceuticals for the treatment of endometriosis and uterine fibroids. It is a potent and highly selective partial agonist of the progesterone receptor (PR). As of 2017, the drug is in phase II clinical trials for the aforementioned indications.
Lonaprisan is a synthetic, steroidal antiprogestogen which was under development by Bayer HealthCare Pharmaceuticals for the treatment of endometriosis, dysmenorrhea, and breast cancer but was discontinued. It is a potent and highly selective silent antagonist of the progesterone receptor (PR). The drug reached phase II clinical trials prior to its discontinuation.
Esaxerenone is a nonsteroidal antimineralocorticoid which was discovered by Exelixis and developed by Daiichi Sankyo Company and is approved in Japan for the treatment of hypertension. It acts as a highly selective silent antagonist of the mineralocorticoid receptor (MR), the receptor for aldosterone, with greater than 1,000-fold selectivity for this receptor over other steroid hormone receptors, and 4-fold and 76-fold higher affinity for the MR relative to the existing antimineralocorticoids spironolactone and eplerenone. As of January 2019, esaxerenone is in phase III clinical trials for diabetic nephropathies.
Dagrocorat is a nonsteroidal but steroid-like selective glucocorticoid receptor modulator (SGRM) which was under development for the treatment of rheumatoid arthritis but was never marketed. It is described as a partial agonist and "dissociable" agonist of the glucocorticoid receptor. The drug reached phase I clinical trials prior to the discontinuation of its development. The C2α dihydrogen phosphate ester of dagrocorat, fosdagrocorat, was also under investigation, but its development was terminated as well.
Fosdagrocorat is a nonsteroidal but steroid-like selective glucocorticoid receptor modulator (SGRM) which was under development for the treatment of rheumatoid arthritis but was never marketed. It is the C2 dihydrogen phosphate ester of dagrocorat, and acts as a prodrug of dagrocorat with improved pharmacokinetics. The drug reached phase II clinical trials prior to the discontinuation of its development.
6β-Hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS) is a steroidal antimineralocorticoid of the spirolactone group and a major active metabolite of spironolactone. Other important metabolites of spironolactone include 7α-thiospironolactone, 7α-thiomethylspironolactone, and canrenone (SC-9376).
7α-Thiospironolactone is a steroidal antimineralocorticoid and antiandrogen of the spirolactone group and a minor active metabolite of spironolactone. Other important metabolites of spironolactone include 7α-thiomethylspironolactone, 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (SC-9376).
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.
EM-5854 is a steroidal antiandrogen which was under development by Endoceutics, Inc. for the treatment of prostate cancer. It was first described in a patent in 2008, and was further characterized in 2012. EM-5854 reached phase I/II clinical trials for the treatment of prostate cancer but development was discontinued in March 2019.
β-LGND2, also known as ERβ-selective ligand 2 or as GTx-878, is a synthetic nonsteroidal estrogen and selective ERβ agonist which was under development by GTx for the treatment of benign prostatic hyperplasia, prostatitis, and rheumatoid arthritis but was never marketed. It shows approximately 25-fold selectivity for activation of the ERβ over the ERα (EC50Tooltip half-maximal effective concentration = 2 nM and 52 nM, respectively). β-LGND2 is an isoquinolinone derivative.
Pyrilutamide is a nonsteroidal antiandrogen (NSAA) – specifically, a selective high-affinity silent antagonist of the androgen receptor (AR) – which is under development by Suzhou Kintor Pharmaceuticals, inc., a subsidiary of Kintor Pharmaceutical Limited, for the potential treatment of androgenic alopecia As of October 2022, it is in phase 3 clinical trials for androgenic alopecia and phase 2 trials for acne.
