Nonsteroidal antiandrogen
| Nonsteroidal antiandrogen | ||
|---|---|---|
Chemical class Nonsteroidal | | |
| Legal status | ||
| In Wikidata | ||
A nonsteroidal antiandrogen (NSAA) is an
full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens like testosterone and dihydrotestosterone (DHT).[2][3] NSAAs are used in the treatment of androgen-dependent conditions in men and women.[2] They are the converse of steroidal antiandrogens (SAAs), which are antiandrogens that are steroids and are structurally related to testosterone.[2][3]
Medical uses
NSAAs are used in clinical medicine for the following indications:[2]
- Prostate cancer in men
- seborrhea, and pattern hair loss(androgenic alopecia) in women
- Hyperandrogenism, such as due to polycystic ovary syndrome or congenital adrenal hyperplasia, in women
- As a component of transgender women[5]
- Precocious puberty in boys
- Priapism in men
Available forms
| Generic name | Class | Type | Brand name(s) | Route(s) | Launch | Status | Hitsa |
|---|---|---|---|---|---|---|---|
| Aminoglutethimide | Nonsteroidal | Androgen synthesis inhibitor | Cytadren, Orimeten | Oral | 1960 | Availableb | 222,000 |
| Apalutamide | Nonsteroidal | AR antagonist | Erleada | Oral | 2018 | Available | 50,400 |
| Bicalutamide | Nonsteroidal | AR antagonist | Casodex | Oral | 1995 | Available | 754,000 |
| Enzalutamide | Nonsteroidal | AR antagonist | Xtandi | Oral | 2012 | Available | 328,000 |
| Flutamide | Nonsteroidal | AR antagonist | Eulexin | Oral | 1983 | Available | 712,000 |
| Ketoconazole | Nonsteroidal | Androgen synthesis inhibitor and weak AR antagonist | Nizoral, others | Oral, topical | 1981 | Available | 3,650,000 |
| Nilutamide | Nonsteroidal | AR antagonist | Anandron, Nilandron | Oral | 1987 | Available | 132,000 |
| Topilutamide | Nonsteroidal | AR antagonist | Eucapil | Topical | 2003 | Availableb | 36,300 |
| Footnotes: a = Hits = Google Search hits (as of February 2018). b = Availability limited / mostly discontinued. Class: Steroidal = Steroidal antiandrogen. Nonsteroidal = Nonsteroidal antiandrogen. Sources: See individual articles. | |||||||
Pharmacology
Unlike SAAs, NSAAs have little or no capacity to activate the AR, show no off-target hormonal activity such as
antigonadotropic effects.[2] For these reasons, they have improved efficacy and selectivity as antiandrogens and do not lower androgen levels, instead acting solely by directly blocking the actions of androgens at the level of their biological target, the AR.[2]
List of NSAAs
Marketed
First-generation
- elevated liver enzymes and hepatotoxicityand the availability of safer agents.
- visual disturbances, and alcohol intolerance.
- safety.
- Topilutamide (Eucapil): Also known as fluridil. Marketed as a topical medication for the treatment of pattern hair loss (androgenic alopecia) in the Czech Republic and Slovakia. Limited availability and lack of an oral formulation for systemic use make it a very little-known drug.[9]
Second-generation
- Apalutamide (Erleada): Marketed for the treatment of prostate cancer. Very similar to enzalutamide, but with reduced central nervous system distribution and hence is expected to have a reduced risk of seizures and other central side effects.
- on-patent with no genericavailability and hence is very expensive.
- terminal half-lifeand lower potency.
Miscellaneous
- H2 receptor antagonist that also shows very weak activity as an AR antagonist. Also inhibits cytochrome P450 enzymes and thereby inhibits hepatic estradiol metabolism and increases circulating estradiol levels. It has been investigated in the treatment of hirsutism but showed minimal effectiveness. Sometimes causes gynecomastiaas a rare side effect.
Nonsteroidal androgen synthesis inhibitors like ketoconazole can also be described as "NSAAs", although the term is usually reserved to describe AR antagonists.
Not marketed
Under development
- Proxalutamide (GT-0918): A second-generation NSAA. It is under development for the treatment of prostate cancer. Similar to enzalutamide and apalutamide, but with increased efficacy as an AR antagonist, little or no central nervous system distribution, and no induction of seizures in animals.
- Seviteronel (VT-464) is a nonsteroidal androgen biosynthesis inhibitor which is under development for the treatment of prostate cancer.
Development discontinued
- Cioteronel (CPC-10997; Cyoctol, Ethocyn, X-Andron): A structurally unique first-generation NSAA. It was under development as an oral medication for the treatment of benign prostatic hyperplasia and as a topical medication for the treatment of acne and pattern hair loss. It reached phase II and phase III clinical trials for these indications prior to discontinuation due to insufficient effectiveness.
- Inocoterone acetate (RU-38882, RU-882): A steroid-like NSAA. It was under development as a topical medication for the treatment of acne but was discontinued due to insufficient effectiveness in clinical trials.
- RU-58841 (PSK-3841, HMR-3841): A first-generation NSAA related to nilutamide. It was under development as a topical medication for the treatment of acne and pattern hair loss but its development was discontinued during phase I clinical trials.
See also
- Selective androgen receptor modulator
- N-Terminal domain antiandrogen
- Discovery and development of antiandrogens
- Nonsteroidal estrogen
References
Further reading
- Teutsch G, Goubet F, Battmann T, Bonfils A, Bouchoux F, Cerede E, Gofflo D, Gaillard-Kelly M, Philibert D (1994). "Non-steroidal antiandrogens: synthesis and biological profile of high-affinity ligands for the androgen receptor". J. Steroid Biochem. Mol. Biol. 48 (1): 111–9. S2CID 31404295.
- Singh SM, Gauthier S, Labrie F (2000). "Androgen receptor antagonists (antiandrogens): structure-activity relationships". Curr. Med. Chem. 7 (2): 211–47. PMID 10637363.
- Iversen P, Melezinek I, Schmidt A (2001). "Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function". BJU Int. 87 (1): 47–56. PMID 11121992.
- Klotz L, Schellhammer P (2005). "Combined androgen blockade: the case for bicalutamide". Clin Prostate Cancer. 3 (4): 215–9. PMID 15882477.
- Gao W, Kim J, Dalton JT (2006). "Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor ligands". Pharm. Res. 23 (8): 1641–58. PMID 16841196.
- Kolvenbag, Geert J. C. M.; Furr, Barrington J. A. (2009). "Nonsteroidal Antiandrogens". In V. Craig Jordan; Barrington J. A. Furr (eds.). Hormone Therapy in Breast and Prostate Cancer. Humana Press. pp. 347–368. ISBN 978-1-60761-471-5.
- Liu B, Su L, Geng J, Liu J, Zhao G (2010). "Developments in nonsteroidal antiandrogens targeting the androgen receptor". ChemMedChem. 5 (10): 1651–61. S2CID 23228778.
- Kunath F, Grobe HR, Rücker G, Motschall E, Antes G, Dahm P, Wullich B, Meerpohl JJ (2015). "Non-steroidal antiandrogen monotherapy compared with luteinizing hormone-releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer: a Cochrane systematic review". BJU Int. 116 (1): 30–6. S2CID 26204957.
- Kaur P, Khatik GL (2016). "Advancements in Non-steroidal Antiandrogens as Potential Therapeutic Agents for the Treatment of Prostate Cancer". Mini Rev Med Chem. 16 (7): 531–46. PMID 26776222.
External links
Media related to Nonsteroidal antiandrogens at Wikimedia Commons
