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.
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 metastatic prostate cancer (mPC). To a lesser extent, it is used at high doses for locally advanced prostate cancer (LAPC) as a monotherapy without castration. Bicalutamide was also previously used as monotherapy to treat localized prostate cancer (LPC), but authorization for this use was withdrawn following unfavorable trial findings. Besides prostate cancer, bicalutamide is limitedly used in the treatment of excessive hair growth and scalp hair loss in women, as a puberty blocker and component of feminizing hormone therapy for transgender girls and women, to treat gonadotropin-independent early puberty in boys, and to prevent overly long-lasting erections in men. It is taken by mouth.
Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions like acne, excessive hair growth, and high androgen levels in women. It is taken by mouth, usually three times per day.
Nilutamide, sold under the brand names Nilandron and Anandron, is a nonsteroidal antiandrogen (NSAA) which is used in the treatment of prostate cancer. It has also been studied as a component of feminizing hormone therapy for transgender women and to treat acne and seborrhea in women. It is taken by mouth.
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), nonmetastatic castration-resistant prostate cancer, and metastatic castration-sensitive prostate cancer (mCSPC). It is taken by mouth.
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.
RU-58841, also known as PSK-3841 or HMR-3841, is a nonsteroidal antiandrogen (NSAA) which was initially developed in the 1980s by Roussel Uclaf, the French pharmaceutical company from which it received its name. It was formerly under investigation by ProStrakan for potential use as a topical treatment for androgen-dependent conditions including acne, pattern hair loss, and excessive hair growth. The compound is similar in structure to the NSAA RU-58642 but contains a different side-chain. These compounds are similar in chemical structure to nilutamide, which is related to flutamide, bicalutamide, and enzalutamide, all of which are NSAAs similarly. RU-58841 can be synthesized either by building the hydantoin moiety or by aryl coupling to 5,5-dimethylhydantoin.
Darolutamide, sold under the brand name Nubeqa, is an antiandrogen medication which is used in the treatment of non-metastatic castration-resistant prostate cancer in men. It is specifically approved to treat non-metastatic castration-resistant prostate cancer (nmCRPC) in conjunction with surgical or medical castration. The medication is taken by mouth twice per day with food.
Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is specifically indicated for use in conjunction with castration in the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC). It is taken by mouth.
DIMP, or N-(3,5-dimethyl-4-isoxazolylmethyl)phthalimide, is a nonsteroidal antiandrogen (NSAA) structurally related to thalidomide that was first described in 1973 and was never marketed. Along with flutamide, it was one of the earliest NSAAs to be discovered, and for this reason, has been described as a "classical" NSAA. The drug is a selective, competitive, silent antagonist of the AR, although it is described as an "only relatively weak competitor". Its relative binding affinity for the androgen receptor is about 2.6% of that of metribolone. DIMP possesses no androgenic, estrogenic, progestogenic, or antigonadotropic activity, but it does reverse the antigonadotropic effects of testosterone, indicating that, like other pure AR antagonists, it is progonadotropic.
A steroidal antiandrogen (SAA) is an antiandrogen with a steroidal chemical structure. They are typically antagonists of the androgen receptor (AR) and act both by blocking the effects of androgens like testosterone and dihydrotestosterone (DHT) and by suppressing gonadal androgen production. SAAs lower concentrations of testosterone through simulation of the negative feedback inhibition of the hypothalamus. SAAs are used in the treatment of androgen-dependent conditions in men and women, and are also used in veterinary medicine for the same purpose. They are the converse of nonsteroidal antiandrogens (NSAAs), which are antiandrogens that are not steroids and are structurally unrelated to testosterone.
Ketodarolutamide is a nonsteroidal antiandrogen (NSAA) and the major active metabolite of darolutamide, an NSAA which is used in the treatment of prostate cancer in men. Similarly to its parent compound, ketodarolutamide acts as a highly selective, high-affinity, competitive silent antagonist of the androgen receptor (AR). Both agents show much higher affinity and more potent inhibition of the AR relative to the other NSAAs enzalutamide and apalutamide, although they also possess much shorter and comparatively less favorable elimination half-lives. They have also been found not to activate certain mutant AR variants that enzalutamide and apalutamide do activate. Both darolutamide and ketodarolutamide show limited central nervous system distribution, indicating peripheral selectivity, and little or no inhibition or induction of cytochrome P450 enzymes such as CYP3A4, unlike enzalutamide and apalutamide.
5N-Bicalutamide, or 5-azabicalutamide, is a highly potent nonsteroidal antiandrogen (NSAA) which was discovered in 2016. It is a structural modification of bicalutamide differing it from it only by the replacement of a carbon atom with a nitrogen atom in one of its phenyl rings. Similarly to bicalutamide, the drug acts as a selective antagonist of the androgen receptor (AR). However, unlike bicalutamide, it is a reversible covalent antagonist and stays bound to the receptor for a far longer amount of time. As a result of this difference, 5N-bicalutamide has markedly improved potency relative to bicalutamide, with approximately 150-fold higher affinity for the AR (Ki = 0.15 nM versus 22.3 nM) and about 20-fold greater functional inhibition (IC50Tooltip Half-maximal inhibitory concentration = 15 nM versus 310 nM) of the AR. Future studies of 5N-bicalutamide in normal and mutated prostate cancer cells are planned or underway and it is anticipated that N-bicalutamide may be able to overcome resistance. to current antiandrogens that are used in the treatment of prostate cancer.
The medical uses of bicalutamide, a nonsteroidal antiandrogen (NSAA), include the treatment of androgen-dependent conditions and hormone therapy to block the effects of androgens. Indications for bicalutamide include the treatment of prostate cancer in men, skin and hair conditions such as acne, seborrhea, hirsutism, and pattern hair loss in women, high testosterone levels in women, hormone therapy in transgender women, as a puberty blocker to prevent puberty in transgender girls and to treat early puberty in boys, and the treatment of long-lasting erections in men. It may also have some value in the treatment of paraphilias and hypersexuality in men.
Comparison of the nonsteroidal antiandrogen (NSAA) bicalutamide with other antiandrogens reveals differences between the medications in terms of efficacy, tolerability, safety, and other parameters. Relative to the other first-generation NSAAs, flutamide and nilutamide, bicalutamide shows improved potency, efficacy, tolerability, and safety, and has largely replaced these medications in clinical practice. Compared to the second-generation NSAAs, enzalutamide and apalutamide, bicalutamide has inferior potency and efficacy but similar tolerability and safety and a lower propensity for drug interactions.
The pharmacology of bicalutamide is the study of the pharmacodynamic and pharmacokinetic properties of the nonsteroidal antiandrogen (NSAA) bicalutamide. In terms of pharmacodynamics, bicalutamide acts as a selective antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has no capacity to activate the AR. It does not decrease androgen levels and has no other important hormonal activity. The medication has progonadotropic effects due to its AR antagonist activity and can increase androgen, estrogen, and neurosteroid production and levels. This results in a variety of differences of bicalutamide monotherapy compared to surgical and medical castration, such as indirect estrogenic effects and associated benefits like preservation of sexual function and drawbacks like gynecomastia. Bicalutamide can paradoxically stimulate late-stage prostate cancer due to accumulated mutations in the cancer. When used as a monotherapy, bicalutamide can induce breast development in males due to its estrogenic effects. Unlike other kinds of antiandrogens, it may have less adverse effect on the testes and fertility.
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.
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.
