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 (INN), 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.
Afimoxifene is a selective estrogen receptor modulator (SERM) of the triphenylethylene group and an active metabolite of tamoxifen. The drug is under development under the tentative brand name TamoGel as a topical gel for the treatment of hyperplasia of the breast. It has completed a phase II clinical trial for cyclical mastalgia, but further studies are required before afimoxifene can be approved for this indication and marketed.
Aticaprant is a selective antagonist of the κ-opioid receptor (KOR) which was originally developed by Eli Lilly and is now under development by Janssen Pharmaceuticals for the treatment of major depressive disorder and smoking withdrawal.
Seltorexant (former developmental code names MIN-202, JNJ-42847922, JNJ-922) is a selective, small-molecule antagonist of the OX2 receptor that is under development by Minerva Neurosciences and Johnson & Johnson's Janssen Pharmaceuticals for the treatment of insomnia and major depressive disorder (MDD). As of December 2015, it is in phase II clinical trials for both insomnia and major depressive disorder.
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.
Ralaniten acetate is a first-in-class antiandrogen that targets the N-terminal domain (NTD) of the androgen receptor (AR) developed by ESSA Pharmaceuticals and was under investigation for the treatment of prostate cancer. This mechanism of action is believed to allow the drug to block signaling from the AR and its splice variants. EPI-506 is a derivative of bisphenol A and a prodrug of ralaniten (EPI-002), one of the four stereoisomers of EPI-001, and was developed as a successor of EPI-001. The drug reached phase I/II prior to the discontinuation of its development. It showed signs of efficacy in the form of prostatic specific antigen (PSA) decreases (4–29%) predominantly at higher doses (≥1,280 mg) in some patients but also caused side effects and was discontinued by its developer in favor of next-generation AR NTD inhibitors with improved potency and tolerability.
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 (INN) 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.
7α-Thiomethylspironolactone is a steroidal antimineralocorticoid and antiandrogen of the spirolactone group and the major active metabolite of spironolactone. Other important metabolites of spironolactone include 7α-thiospironolactone, 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (SC-9376).
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).
RD-162 is a second-generation nonsteroidal antiandrogen (NSAA) which was developed for the treatment of prostate cancer but was never marketed. It acts as a potent and selective silent antagonist of the androgen receptor (AR). The drug is a diarylthiohydantoin derivative. It is closely related to enzalutamide and apalutamide. Both RD-162 and enzalutamide show 5- to 8-fold higher affinity for the AR than the first-generation NSAA bicalutamide, and only 2- to 3-fold lower affinity than dihydrotestosterone (DHT), the major endogenous ligand of the receptor in the prostate gland.
BMS-641988 is a nonsteroidal antiandrogen which was developed by Bristol-Myers Squibb for the treatment of prostate cancer but was never marketed. It acts as a potent competitive antagonist of the androgen receptor (AR) (Ki = 10 nM; IC50 = 56 nM). The drug was found to have 20-fold higher affinity for the AR than bicalutamide in MDA-MB-453 cells, and showed 3- to 7-fold the antiandrogenic activity of bicalutamide in vitro. It may have some weak partial agonist activity at the androgen receptor. BMS-641988 is transformed by CYP3A4 into BMS-570511, and this metabolite is then reduced to BMS-501949 by cytosolic reductases. All three compounds show similar antiandrogenic activity. In addition to its antiandrogenic activity, BMS-641988 shows activity as a negative allosteric modulator of the GABAA receptor, and can produce seizures in animals at sufficiently high doses. It also shows some drug-induced QT prolongation. BMS-641988 reached phase I clinical trials prior to the discontinuation of its development. The clinical development of BMS-641988 was terminated due to the occurrence of a seizure in a patient during a phase I study.
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.
Daridorexant (developmental code name ACT-541468), formerly known as nemorexant, is a dual orexin receptor antagonist (DORA) which was originated by Actelion Pharmaceuticals and is under development by Idorsia Pharmaceuticals for the treatment of insomnia. It acts as a selective dual antagonist of the orexin receptors OX1 and OX2. The medication has a relatively short elimination half-life of 6 to 10 hours. As of April 2020, daridorexant has passed its first phase III clinical trial for the treatment of insomnia.
