Nonsteroidal antiandrogen

Last updated
Nonsteroidal antiandrogen
Drug class
Bicalutamide.svg
Bicalutamide, the most widely used nonsteroidal antiandrogen and the most widely used antiandrogen in prostate cancer.
Class identifiers
Synonyms Nonsteroidal androgen receptor antagonists
Use Prostate cancer; Acne; Hirsutism; Seborrhea; Pattern hair loss; Hyperandrogenism; Transgender hormone therapy; Male precocious puberty; Priapism
ATC code L02BB
Biological target Androgen receptor
Chemical class Nonsteroidal
Legal status
In Wikidata

A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. [1] [2] [3] 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). [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]

Contents

Medical uses

NSAAs are used in clinical medicine for the following indications: [2]

Available forms

Antiandrogens marketed for clinical or veterinary use
Generic nameClassTypeBrand name(s)Route(s)LaunchStatus
Aminoglutethimide NonsteroidalAndrogen synthesis inhibitorCytadren, OrimetenOral1960Availableb
Apalutamide NonsteroidalAR antagonistErleadaOral2018Available
Bicalutamide NonsteroidalAR antagonistCasodexOral1995Available
Enzalutamide NonsteroidalAR antagonistXtandiOral2012Available
Flutamide NonsteroidalAR antagonistEulexinOral1983Available
Ketoconazole NonsteroidalAndrogen synthesis inhibitor and weak AR antagonistNizoral, othersOral, topical1981Available
Nilutamide NonsteroidalAR antagonistAnandron, NilandronOral1987Available
Topilutamide NonsteroidalAR antagonistEucapilTopical2003Availableb
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 progestogenic, glucocorticoid, or antimineralocorticoid activity, and lack 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

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.
  • Enzalutamide (Xtandi): Marketed for the treatment of prostate cancer. More effective than the first-generation NSAAs due to increased efficacy and potency and shows no risk of elevated liver enzymes or hepatotoxicity. However, it has a small (1%) risk of seizures and has central nervous system side effects like anxiety and insomnia due to off-target inhibition of the GABAA receptor that the first-generation NSAAs do not have. In addition, it has prominent drug interactions due to moderate to strong induction of multiple cytochrome P450 enzymes. Currently on-patent with no generic availability and hence is very expensive.
  • Darolutamide (Nubeqa): Marketed for the treatment of prostate cancer. Structurally distinct from enzalutamide, apalutamide, and other NSAAs. Relative to enzalutamide and apalutamide, shows greater efficacy as an AR antagonist, improved activity against mutated AR variants in prostate cancer, little or no inhibition or induction of cytochrome P450 enzymes, and little or no central nervous system distribution. However, has a much shorter terminal half-life and lower potency.

Miscellaneous

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

References

  1. 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. doi:10.1007/978-1-59259-152-7_16. ISBN   978-1-60761-471-5.
  2. 1 2 3 4 5 6 7 Singh SM, Gauthier S, Labrie F (2000). "Androgen receptor antagonists (antiandrogens): structure-activity relationships". Curr. Med. Chem. 7 (2): 211–47. doi:10.2174/0929867003375371. PMID   10637363.
  3. 1 2 3 4 5 Migliari R, Muscas G, Murru M, Verdacchi T, De Benedetto G, De Angelis M (1999). "Antiandrogens: a summary review of pharmacodynamic properties and tolerability in prostate cancer therapy". Arch Ital Urol Androl. 71 (5): 293–302. PMID   10673793.
  4. 1 2 3 Erem C (2013). "Update on idiopathic hirsutism: diagnosis and treatment". Acta Clin Belg. 68 (4): 268–74. doi:10.2143/ACB.3267. PMID   24455796. S2CID   39120534.
  5. 1 2 Gooren LJ (2011). "Clinical practice. Care of transsexual persons". N. Engl. J. Med. 364 (13): 1251–7. doi:10.1056/NEJMcp1008161. PMID   21449788.
  6. 1 2 Kenny B, Ballard S, Blagg J, Fox D (1997). "Pharmacological options in the treatment of benign prostatic hyperplasia". J. Med. Chem. 40 (9): 1293–315. doi:10.1021/jm960697s. PMID   9135028.
  7. Reiter EO, Norjavaara E (2005). "Testotoxicosis: current viewpoint". Pediatr Endocrinol Rev. 3 (2): 77–86. PMID   16361981.
  8. Yuan J, Desouza R, Westney OL, Wang R (2008). "Insights of priapism mechanism and rationale treatment for recurrent priapism". Asian J. Androl. 10 (1): 88–101. doi: 10.1111/j.1745-7262.2008.00314.x . PMID   18087648.
  9. Sovak, Milos; Seligson, Allen L.; Kucerova, Renata; Bienova, Marie; Hajduch, Marian; Bucek, Milan (August 2002). "Fluridil, a Rationally Designed Topical Agent for Androgenetic Alopecia: First Clinical Experience". Dermatologic Surgery. 28 (8): 678–685. doi:10.1046/j.1524-4725.2002.02017.x. ISSN   1076-0512. PMID   12174057. S2CID   36439600. Archived from the original on 2023-11-15. Retrieved 2024-02-24.

Further reading