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Nonsteroidal antiandrogen

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Nonsteroidal antiandrogen
Drug class
Bicalutamide, the most widely used nonsteroidal antiandrogen and the most widely used antiandrogen in prostate cancer.
Class identifiers
SynonymsNonsteroidal androgen receptor antagonists
UseProstate cancer; Acne; Hirsutism; Seborrhea; Pattern hair loss; Hyperandrogenism; Transgender hormone therapy; Male precocious puberty; Priapism
ATC codeL02BB
Biological targetAndrogen receptor
Chemical classNonsteroidal
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]

Medical uses

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

Available forms

Antiandrogens marketed for clinical or veterinary use
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 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. ^ a b c d e f g 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. ^ a b c d e 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. ^ a b c 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. ^ a b Gooren LJ (2011). "Clinical practice. Care of transsexual persons". N. Engl. J. Med. 364 (13): 1251–7. doi:10.1056/NEJMcp1008161. PMID 21449788.
  6. ^ a b 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.

Further reading

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