Benorterone

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Benorterone
Benorterone.svg
Clinical data
Other namesSKF-7690; FC-612; 17α-Methyl-B-nortestosterone; 17α-Methyl-B-norandrost-4-en-17β-ol-3-one
Routes of
administration 		By mouth, topical [1]
Drug class Steroidal antiandrogen
ATC code
  • None
Identifiers
  • (3S,3aS,5aS,5bR,10aR,10bS)-3-hydroxy-3,3a,5b-trimethyl-1,2,4,5,5a,6,7,10,10a,10b-decahydrocyclopenta[a]fluoren-8-one
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C19H28O2
Molar mass 288.431 g·mol−1
3D model (JSmol)
  • CC12CCC(=O)C=C1CC3C2CCC4(C3CCC4(C)O)C
  • InChI=InChI=1S/C19H28O2/c1-17-7-4-13(20)10-12(17)11-14-15(17)5-8-18(2)16(14)6-9-19(18,3)21/h10,14-16,21H,4-9,11H2,1-3H3/t14-,15+,16+,17+,18+,19+/m1/s1
  • Key:RQETXCPBBLHUIB-UGCZWRCOSA-N

Benorterone, also known by its developmental code name SKF-7690 and as 17α-methyl-B-nortestosterone, is a steroidal antiandrogen which was studied for potential medical use but was never marketed. [2] [3] It was the first known antiandrogen to be studied in humans. [1] It is taken by mouth or by application to skin. [1]

Contents

Pharmacology

Pharmacodynamics

Benorterone is an antiandrogen, or an antagonist of the androgen receptor (AR), the biological target of the androgen sex hormones testosterone and dihydrotestosterone. [3] In one study, the affinity of benorterone for the AR was found to be about 5-fold greater than that of cyproterone acetate in rat prostate cytosol; the Ki values were 0.7 nM for benorterone and 3.7 nM for cyproterone acetate, which were 243% and 46% of those of testosterone (Ki = 1.7 nM), respectively. [4] [5] However, another study found that benorterone had only 11% of the affinity of dihydrotestosterone for the androgen receptor. [4] Although an antiandrogen, benorterone actually is a very weak partial agonist of the AR and has been reported to possess weak androgenic activity. [6] The same is true for cyproterone acetate and other steroidal antiandrogens. [7] [8]

Unlike certain other steroidal antiandrogens such as cyproterone acetate, benorterone is not also a progestogen, instead being described as a selective and pure AR antagonist similarly to nonsteroidal antiandrogens such as flutamide and bicalutamide. [9] [3] However, although it is described as not being a progestogen, benorterone was found to produce "a highly variable decrease in plasma testosterone levels," indicating that it has weak antigonadotropic effects. [3] [10] The reasons for this are unclear, as other pure antiandrogens such as cyproterone (not cyproterone acetate) and flutamide do not do this and instead produce consistent increases in testosterone levels. [11] However, it is notable that the anabolic steroid methyltestosterone, which benorterone differs from in chemical structure only by the removal of a carbon atom in the B ring, is aromatized into the estrogen methylestradiol and has potent estrogenic activity. [12] Estrogens are antigonadotropic similarly to androgens and progestogens and are likewise able to suppress testosterone levels. [13] In accordance, the compound corresponding to what would be the aromatized form of benorterone, 17α-methyl-B-norestradiol, has been described and has been reported to possess estrogenic activity, although the aromatization of benorterone has not been assessed. [14]

A couple of studies found that prothrombin levels decreased by 50% in some patients treated with benorterone, although a causal relationship between this change and benorterone could not be shown. [3]

Pharmacokinetics

Benorterone is active orally and topically and has been studied by both of these routes of administration. [1]

Chemistry

Benorterone, also known as 17α-methyl-B-nortestosterone or as 17α-methyl-B-norandrost-4-en-17β-ol-3-one, is a synthetic androstane steroid and a derivative of testosterone. [2] Specifically, it is the C17α methyl and B-nor analogue of testosterone and the B-nor analogue of methyltestosterone. [2] Other testosterone-derived steroidal antiandrogens include abiraterone acetate, BOMT, delanterone, dienogest, galeterone, metogest, mifepristone, oxendolone, rosterolone, topterone, trimethyltrienolone, and zanoterone, while progesterone-derived steroidal antiandrogens include examples like cyproterone and cyproterone acetate. [2]

History

Benorterone was developed in the late 1950s, was first reported to possess antiandrogenic activity in 1964, and was investigated in clinical trials in the mid-to-late 1960s. [2] [1] [6] It was the first known antiandrogen to be studied in humans. [1] The drug was found to be effective in the treatment of acne, seborrhea, and hirsutism in women. [3] [15] [16] In addition, unlike progestogenic antiandrogens such as cyproterone acetate, it seldom produced side effects in women and did not affect menstruation. [3] However, in males, benorterone was not effective for acne, and produced high rates of gynecomastia (in 12 out of 13 or 92% of young men treated with 75 to 300 mg/day benorterone). [17] [18] [19] Shortly following the observance of this side effect, it was withdrawn from clinical studies. [3] [1] Subsequently, cyproterone acetate, which has a greatly reduced risk of gynecomastia by virtue of its concomitant progestogenic and antigonadotropic actions (which results in suppression of estrogen levels), was developed instead and was introduced for medical use in 1973. [20] In addition, spironolactone, a steroidal antimineralocorticoid that was introduced for medical use in 1959, was discovered to possess potent antiandrogenic activity in 1969, and became widely used clinically as an antiandrogen after its first use in an androgen-dependent condition in 1978. [21] [22] [23]

Society and culture

Generic names

Benorterone is the generic name of the drug and its INN Tooltip International Nonproprietary Name and USAN Tooltip United States Adopted Name. [2] It is also known by its developmental code names SKF-7690 and FC-612. [2]

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Hirsutism is excessive body hair on parts of the body where hair is normally absent or minimal. The word is from early 17th century: from Latin hirsutus meaning "hairy". It usually refers to a male pattern of hair growth in a female that may be a sign of a more serious medical condition, especially if it develops well after puberty. Cultural stigma against hirsutism can cause much psychological distress and social difficulty. Discrimination based on facial hirsutism often leads to the avoidance of social situations and to symptoms of anxiety and depression.

<span class="mw-page-title-main">Antiandrogen</span> Class of pharmaceutical drugs

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.

<span class="mw-page-title-main">Progestogen (medication)</span> Medication producing effects similar to progesterone

A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

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<span class="mw-page-title-main">Chlormadinone acetate</span> Chemical compound

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<span class="mw-page-title-main">Cyproterone acetate</span> Chemical compound

Cyproterone acetate (CPA), sold alone under the brand name Androcur or with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the treatment of androgen-dependent conditions such as acne, excessive body hair growth, early puberty, and prostate cancer, as a component of feminizing hormone therapy for transgender women, and in birth control pills. It is formulated and used both alone and in combination with an estrogen. CPA is taken by mouth one to three times per day.

<span class="mw-page-title-main">Cyproterone</span> Chemical compound

Cyproterone, also known by its developmental code name SH-80881, is a steroidal antiandrogen which was studied in the 1960s and 1970s but was never introduced for medical use. It is an analogue of cyproterone acetate (CPA), an antiandrogen, progestin, and antigonadotropin which was introduced instead of cyproterone and is widely used as a medication. Cyproterone and CPA were among the first antiandrogens to be developed.

<span class="mw-page-title-main">Anagestone acetate</span> Chemical compound

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<span class="mw-page-title-main">Inocoterone acetate</span> Chemical compound

Inocoterone acetate is a steroid-like nonsteroidal antiandrogen (NSAA) that was developed for topical administration to treat acne but was never marketed. It is the acetate ester of inocoterone, which is less potent in comparison. Inocoterone acetate is actually not a silent antagonist of the androgen receptor but rather a weak partial agonist, similarly to steroidal antiandrogens like cyproterone acetate.

<span class="mw-page-title-main">BOMT</span> Chemical compound

BOMT, also known by its developmental code name Ro 7-2340 and as 6α-bromo-4-oxa-17α-methyl-5α-dihydrotestosterone, is a synthetic steroidal antiandrogen which was first developed in 1970 and was never marketed for medical use. It is the 6α-brominated, 4-oxygenated, and 17α-methylated derivative of the androgen dihydrotestosterone (DHT). Along with benorterone, cyproterone, and flutamide, BOMT was among the earliest antiandrogens to be developed and extensively studied, although it is less well-documented in comparison to the others. BOMT has been investigated clinically in the treatment of benign prostatic hyperplasia, though development for this use did not continue. There was also interest in BOMT for the potential applications of acne, pattern hair loss, and possibly prostate cancer, but it was not developed for these indications either.

<span class="mw-page-title-main">Trimethyltrienolone</span> Chemical compound

Trimethyltrienolone (TMT), also known by its developmental code name R-2956 or RU-2956, is an antiandrogen medication which was never introduced for medical use but has been used in scientific research.

<span class="mw-page-title-main">Steroidal antiandrogen</span> Class of compounds

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.

<span class="mw-page-title-main">Dimethandrolone</span> Chemical compound

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<span class="mw-page-title-main">Ethyltestosterone</span> Synthetic anabolic steroid

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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.

<span class="mw-page-title-main">Pharmacology of cyproterone acetate</span>

The pharmacology of cyproterone acetate (CPA) concerns the pharmacology of the steroidal antiandrogen and progestin medication cyproterone acetate.

<span class="mw-page-title-main">Ethinylestradiol/cyproterone acetate</span> Combination drug

Ethinylestradiol/cyproterone acetate (EE/CPA), also known as co-cyprindiol and sold under the brand names Diane and Diane-35 among others, is a combination of ethinylestradiol (EE), an estrogen, and cyproterone acetate (CPA), a progestin and antiandrogen, which is used as a birth control pill to prevent pregnancy in women. It is also used to treat androgen-dependent conditions in women such as acne, seborrhea, excessive facial/body hair growth, scalp hair loss, and high androgen levels associated with ovaries with cysts. The medication is taken by mouth once daily for 21 days, followed by a 7-day free interval.

References

  1. 1 2 3 4 5 6 7 Jacobs HS (1979). Advances in gynaecological endocrinology: proceedings of the Sixth Study Group of the Royal College of Obstetricians and Gynaecologists, 18th and 19th October, 1978. The College. p. 367. ISBN   978-0-87489-225-3. Limited clinical experience also exists with benorterone, the first anti-androgen tried in man, and with free cyproterone. In the late sixties benorterone was reported to give promising results in 93 androgenized women but was soon withdrawn from clinical trial, mainly because of the development of gynaecomastia in the male. As a big advantage compared with CPA, it was found to be effective not only orally but also topically. Free cyproterone, on the other hand, proved to be without clinical value for reasons that cannot be discussed here. Thus we are left with CPA as the only anti-androgen that is already on the market in several countries.
  2. 1 2 3 4 5 6 7 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 129–. ISBN   978-1-4757-2085-3.
  3. 1 2 3 4 5 6 7 8 Gräf KJ, Brotherton J, Neumann F (27 November 2013). "Clinical Uses of Anti Androgens (other than for hypersexuality and sexual deviations)". In Hughes A, Hasan SH, Oertel GW, Voss HE, Bahner F, Neumann F, et al. (eds.). Androgens II and Antiandrogens / Androgene II und Antiandrogene. Springer Science & Business Media. pp. 491–492, 516–517, 523. ISBN   978-3-642-80859-3.
  4. 1 2 Tindall DJ, Chang CH, Lobl TJ, Cunningham GR (1984). "Androgen antagonists in androgen target tissues". Pharmacology & Therapeutics. 24 (3): 367–400. doi:10.1016/0163-7258(84)90010-X. PMID   6205409.
  5. ↑ Stárka L, Sulcová J, Broulik PD, Joska J, Fajkos J, Doskocil M (September 1977). "Screening for antiandrogenic activity of some 4,5-cyclo-A-homo-B-nor-and-androstane derivatives". Journal of Steroid Biochemistry. 8 (9): 939–941. doi:10.1016/0022-4731(77)90190-X. PMID   916678.
  6. 1 2 Pria SD, Greenblatt RB, Mahesh VB (April 1969). "An antiandrogen in acne and idiopathic hirsutism". The Journal of Investigative Dermatology. 52 (4): 348–350. doi: 10.1038/jid.1969.58 . PMID   4238084.
  7. ↑ Figg WD, Chau CH, Small EJ (14 September 2010). Drug Management of Prostate Cancer. Springer Science & Business Media. pp. 71–. ISBN   978-1-60327-829-4.
  8. ↑ Fritz MA, Speroff L (2011). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. pp. 80–. ISBN   978-0-7817-7968-5.
  9. ↑ Saunders HL, Holden K, Kerwin JF (1964). "The anti-androgenic activity of 17α-methyl-B-nortestosterone (SK&F 7690)". Steroids. 3 (6): 687–698. doi:10.1016/0039-128X(64)90117-5. ISSN   0039-128X.
  10. ↑ Mahesh VB (January 2012). "Hirsutism, virilism, polycystic ovarian disease, and the steroid-gonadotropin-feedback system: a career retrospective". American Journal of Physiology. Endocrinology and Metabolism. 302 (1): E4–E18. doi:10.1152/ajpendo.00488.2011. PMC   3328092 . PMID   22028409.
  11. ↑ Becker KL (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 1196–. ISBN   978-0-7817-1750-2.
  12. ↑ Llewellyn W (2011). Anabolics. Molecular Nutrition Llc. pp. 533–. ISBN   978-0-9828280-1-4.
  13. ↑ Oettel M (6 December 2012). "Estrogens and Antiestrogens in the Male". In Oettel M, Schillinger E (eds.). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. pp. 505–574 (543). ISBN   978-3-642-60107-1.
  14. ↑ US 3377361,Fare LR, Kerwin JR, Kinney RW,"B-norestrogens",issued 9 April 1968, assigned to Smith Kline and French Laboratories Ltd.
  15. ↑ Zarate A, Mahesh VB, Greenblatt RB (December 1966). "Effect of an antiandrogen, 17-alpha-methyl-B-nortestosterone, on acne and hirsutism". The Journal of Clinical Endocrinology and Metabolism. 26 (12): 1394–1398. doi:10.1210/jcem-26-12-1394. PMID   4225258.
  16. ↑ Orfanos CE, Happle R (1990). Hair and Hair Diseases. Springer Science & Business Media. pp. 1195–. ISBN   978-3-642-74612-3.
  17. ↑ Hammerstein J (1990). "Antiandrogens: Clinical Aspects". Hair and Hair Diseases. Springer. pp. 827–886. doi:10.1007/978-3-642-74612-3_35. ISBN   978-3-642-74614-7.
  18. ↑ Caplan RM (September 1967). "Gynecomastia from a non-estrogenic anti-androgen". The Journal of Clinical Endocrinology and Metabolism. 27 (9): 1348–1349. doi:10.1210/jcem-27-9-1348. PMID   4227085.
  19. ↑ Sobrinho LG, Kase N, Grunt JA (October 1971). "Spontaneous pubertal breast growth in a castrated patient with the syndrome of testicular feminization". The Yale Journal of Biology and Medicine. 44 (2): 225–229. PMC   2591727 . PMID   5123057.
  20. ↑ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 1182–. ISBN   978-0-8155-1856-3.
  21. ↑ Steelman SL, Brooks JR, Morgan ER, Patanelli DJ (October 1969). "Anti-androgenic activity of spironolactone". Steroids. 14 (4): 449–450. doi:10.1016/S0039-128X(69)80007-3. PMID   5344274.
  22. ↑ Ober KP, Hennessy JF (November 1978). "Spironolactone therapy for hirsutism in a hyperandrogenic woman". Annals of Internal Medicine. 89 (5 Pt 1): 643–644. doi:10.7326/0003-4819-89-5-643. PMID   717935.
  23. ↑ Curtis M, Antoniewicz L, Linares ST (2014). Glass' Office Gynecology. Lippincott Williams & Wilkins. pp. 47–. ISBN   978-1-60831-820-9.
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