{{Short description|Chemical compound}} {{Use dmy dates|date=November 2017}} {{Drugbox | Verifiedfields = | Watchedfields = | verifiedrevid = | IUPAC_name = (3''S'',3a''S'',5a''S'',5b''R'',10a''R'',10b''S'')-3-hydroxy-3,3a,5b-trimethyl-1,2,4,5,5a,6,7,10,10a,10b-decahydrocyclopenta[''a'']fluoren-8-one | image = Benorterone.svg | image_class = skin-invert-image | width = 225px

<!--Clinical data--> | tradename = | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_US = <!-- A / B / C / D / X --> | pregnancy_category = | legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> | legal_CA = | legal_UK = | legal_US = | legal_status = | routes_of_administration = By mouth, topical<ref name="JacobsBritain)1979" /> | class = Steroidal antiandrogen

<!--Pharmacokinetic data--> | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion =

<!--Identifiers--> | CAS_number_Ref = | CAS_number = 3570-10-3 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = J339Q7IM54 | CAS_supplemental = | ATC_prefix = None | ATC_suffix = | PubChem = 10039776 | DrugBank_Ref = | DrugBank = | ChemSpiderID_Ref = | ChemSpiderID = 8215340 | synonyms = SKF-7690; FC-612; 17α-Methyl-''B''-nortestosterone; 17α-Methyl-''B''-norandrost-4-en-17β-ol-3-one

<!--Chemical data--> | C=19 | H=28 | O=2 | SMILES = CC12CCC(=O)C=C1CC3C2CCC4(C3CCC4(C)O)C | StdInChI_Ref = | StdInChI = 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 | StdInChIKey_Ref = | StdInChIKey = 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.<ref name="Elks2014">{{cite book | vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies |url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA129 |date=14 November 2014 |publisher=Springer |isbn=978-1-4757-2085-3 |pages=129–}}</ref><ref name="HughesHasan2013">{{cite book | vauthors = Gräf KJ, Brotherton J, Neumann F | chapter = Clinical Uses of Anti Androgens (other than for hypersexuality and sexual deviations) | veditors = Hughes A, Hasan SH, Oertel GW, Voss HE, Bahner F, Neumann F, Steinbeck H, Gräf KJ, Brotherton J, Horn HJ, Wagner RK | display-editors = 6 |title=Androgens II and Antiandrogens / Androgene II und Antiandrogene | chapter-url=https://books.google.com/books?id=7JPsCAAAQBAJ&pg=PA491 |date=27 November 2013 |publisher=Springer Science & Business Media |isbn=978-3-642-80859-3 |pages=491–492, 516–517, 523}}</ref> It was the first known antiandrogen to be studied in humans.<ref name="JacobsBritain)1979" /> It is taken by mouth or by application to skin.<ref name="JacobsBritain)1979" />

==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.<ref name="HughesHasan2013" /> 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 K<sub>i</sub> values were 0.7&nbsp;nM for benorterone and 3.7&nbsp;nM for cyproterone acetate, which were 243% and 46% of those of testosterone (K<sub>i</sub> = 1.7&nbsp;nM), respectively.<ref name="pmid6205409">{{cite journal | vauthors = Tindall DJ, Chang CH, Lobl TJ, Cunningham GR | title = Androgen antagonists in androgen target tissues | journal = Pharmacology & Therapeutics | volume = 24 | issue = 3 | pages = 367–400 | date = 1984 | pmid = 6205409 | doi = 10.1016/0163-7258(84)90010-X }}</ref><ref name="pmid916678">{{cite journal | vauthors = Stárka L, Sulcová J, Broulik PD, Joska J, Fajkos J, Doskocil M | title = Screening for antiandrogenic activity of some 4,5-cyclo-A-homo-B-nor-and-androstane derivatives | journal = Journal of Steroid Biochemistry | volume = 8 | issue = 9 | pages = 939–941 | date = September 1977 | pmid = 916678 | doi = 10.1016/0022-4731(77)90190-X }}</ref> However, another study found that benorterone had only 11% of the affinity of dihydrotestosterone for the androgen receptor.<ref name="pmid6205409"/> Although an antiandrogen, benorterone actually is a very weak partial agonist of the AR and has been reported to possess weak androgenic activity.<ref name="pmid4238084" /> The same is true for cyproterone acetate and other steroidal antiandrogens.<ref name="FiggChau2010">{{cite book| vauthors = Figg WD, Chau CH, Small EJ |title=Drug Management of Prostate Cancer|url=https://books.google.com/books?id=4KDrjeWA5-UC&pg=PA71|date=14 September 2010|publisher=Springer Science & Business Media|isbn=978-1-60327-829-4|pages=71–}}</ref><ref name="FritzSperoff2011">{{cite book | vauthors = Fritz MA, Speroff L |title=Clinical Gynecologic Endocrinology and Infertility|url=https://books.google.com/books?id=Ll73ZsBKLkwC&pg=PA80|year=2011|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-7968-5|pages=80–}}</ref>

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.<ref name="SaundersHolden1964">{{cite journal | vauthors = Saunders HL, Holden K, Kerwin JF |title=The anti-androgenic activity of 17α-methyl-B-nortestosterone (SK&F 7690) |journal=Steroids |volume=3 |issue=6 |year=1964 |pages=687–698 |issn=0039-128X |doi=10.1016/0039-128X(64)90117-5}}</ref><ref name="HughesHasan2013" /> 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.<ref name="HughesHasan2013" /><ref name="pmid22028409">{{cite journal | vauthors = Mahesh VB | title = Hirsutism, virilism, polycystic ovarian disease, and the steroid-gonadotropin-feedback system: a career retrospective | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 302 | issue = 1 | pages = E4–E18 | date = January 2012 | pmid = 22028409 | pmc = 3328092 | doi = 10.1152/ajpendo.00488.2011 }}</ref> 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.<ref name="Becker2001">{{cite book| vauthors = Becker KL |title=Principles and Practice of Endocrinology and Metabolism|url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1196|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=1196–}}</ref> 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.<ref name="Llewellyn2011">{{cite book| vauthors = Llewellyn W |title=Anabolics|url=https://books.google.com/books?id=afKLA-6wW0oC&pg=PT533|year=2011|publisher=Molecular Nutrition Llc|isbn=978-0-9828280-1-4|pages=533–}}</ref> Estrogens are antigonadotropic similarly to androgens and progestogens and are likewise able to suppress testosterone levels.<ref name="OettelSchillinger2012">{{cite book | vauthors = Oettel M | chapter = Estrogens and Antiestrogens in the Male | veditors = Oettel M, Schillinger E |title=Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen| chapter-url = https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA543|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-60107-1|pages=505–574 (543)}}</ref> 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.<ref name="FareKerwin1968">{{cite patent | inventor = Fare LR, Kerwin JR, Kinney RW | country = US | number = 3377361 | title = B-norestrogens | assign1 = Smith Kline and French Laboratories Ltd. | url = https://patents.google.com/patent/US3377361A/en | gdate = 9 April 1968 }}</ref>

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.<ref name="HughesHasan2013" />

===Pharmacokinetics=== Benorterone is active orally and topically and has been studied by both of these routes of administration.<ref name="JacobsBritain)1979" />

==Chemistry== {{See also|Steroidal antiandrogen|List of steroidal antiandrogens}}

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.<ref name="Elks2014" /> Specifically, it is the C17α methyl and ''B''-nor analogue of testosterone and the ''B''-nor analogue of methyltestosterone.<ref name="Elks2014" /> 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.<ref name="Elks2014" />

==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.<ref name="Elks2014" /><ref name="JacobsBritain)1979">{{cite book| vauthors = Jacobs HS |title=Advances in gynaecological endocrinology: proceedings of the Sixth Study Group of the Royal College of Obstetricians and Gynaecologists, 18th and 19th October, 1978|url=https://books.google.com/books?id=waMTAQAAMAAJ|year=1979|publisher=The College|isbn=978-0-87489-225-3|page=367|quote=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.}}</ref><ref name="pmid4238084">{{cite journal | vauthors = Pria SD, Greenblatt RB, Mahesh VB | title = An antiandrogen in acne and idiopathic hirsutism | journal = The Journal of Investigative Dermatology | volume = 52 | issue = 4 | pages = 348–350 | date = April 1969 | pmid = 4238084 | doi = 10.1038/jid.1969.58 | doi-access = free }}</ref> It was the first known antiandrogen to be studied in humans.<ref name="JacobsBritain)1979" /> The drug was found to be effective in the treatment of acne, seborrhea, and hirsutism in women.<ref name="HughesHasan2013" /><ref name="ZarateMahesh1966">{{cite journal | vauthors = Zarate A, Mahesh VB, Greenblatt RB | title = Effect of an antiandrogen, 17-alpha-methyl-B-nortestosterone, on acne and hirsutism | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 26 | issue = 12 | pages = 1394–1398 | date = December 1966 | pmid = 4225258 | doi = 10.1210/jcem-26-12-1394 }}</ref><ref name="OrfanosHapple1990">{{cite book | vauthors = Orfanos CE, Happle R |title=Hair and Hair Diseases |url=https://books.google.com/books?id=k7urBgAAQBAJ&pg=PT1195 |year=1990 |publisher=Springer Science & Business Media |isbn=978-3-642-74612-3 |pages=1195–}}</ref> In addition, unlike progestogenic antiandrogens such as cyproterone acetate, it seldom produced side effects in women and did not affect menstruation.<ref name="HughesHasan2013" /> 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&nbsp;mg/day benorterone).<ref name="Hammerstein1990">{{cite book | vauthors = Hammerstein J | chapter = Antiandrogens: Clinical Aspects | title = Hair and Hair Diseases |year=1990|pages=827–886| publisher = Springer |doi=10.1007/978-3-642-74612-3_35|isbn=978-3-642-74614-7}}</ref><ref name="pmid4227085">{{cite journal | vauthors = Caplan RM | title = Gynecomastia from a non-estrogenic anti-androgen | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 27 | issue = 9 | pages = 1348–1349 | date = September 1967 | pmid = 4227085 | doi = 10.1210/jcem-27-9-1348 }}</ref><ref name="pmid5123057">{{cite journal | vauthors = Sobrinho LG, Kase N, Grunt JA | title = Spontaneous pubertal breast growth in a castrated patient with the syndrome of testicular feminization | journal = The Yale Journal of Biology and Medicine | volume = 44 | issue = 2 | pages = 225–229 | date = October 1971 | pmid = 5123057 | pmc = 2591727 }}</ref> Shortly following the observance of this side effect, it was withdrawn from clinical studies.<ref name="HughesHasan2013" /><ref name="JacobsBritain)1979" /> 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.<ref name="Publishing2013">{{cite book |author=William Andrew Publishing |title=Pharmaceutical Manufacturing Encyclopedia, 3rd Edition |url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1182 |date=22 October 2013 |publisher=Elsevier |isbn=978-0-8155-1856-3 |pages=1182–}}</ref> 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.<ref name="pmid5344274">{{cite journal | vauthors = Steelman SL, Brooks JR, Morgan ER, Patanelli DJ | title = Anti-androgenic activity of spironolactone | journal = Steroids | volume = 14 | issue = 4 | pages = 449–450 | date = October 1969 | pmid = 5344274 | doi = 10.1016/S0039-128X(69)80007-3 }}</ref><ref name="pmid717935">{{cite journal | vauthors = Ober KP, Hennessy JF | title = Spironolactone therapy for hirsutism in a hyperandrogenic woman | journal = Annals of Internal Medicine | volume = 89 | issue = 5 Pt 1 | pages = 643–644 | date = November 1978 | pmid = 717935 | doi = 10.7326/0003-4819-89-5-643 }}</ref><ref name="CurtisAntoniewicz2014">{{cite book| vauthors = Curtis M, Antoniewicz L, Linares ST |title=Glass' Office Gynecology|url=https://books.google.com/books?id=w2AGBAAAQBAJ&pg=PA47|year=2014|publisher=Lippincott Williams & Wilkins|isbn=978-1-60831-820-9|pages=47–}}</ref>

==Society and culture==

===Generic names=== ''Benorterone'' is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}} and {{abbrlink|USAN|United States Adopted Name}}.<ref name="Elks2014" /> It is also known by its developmental code names ''SKF-7690'' and ''FC-612''.<ref name="Elks2014" />

== References == {{Reflist}}

{{Androgen receptor modulators}}

Category:Abandoned drugs Category:Tertiary alcohols Category:Androstanes Category:Antigonadotropins Category:Cyclopentanes Category:Enones Category:Steroidal antiandrogens