Zanoterone

{{Short description|Chemical compound}} {{Drugbox | Verifiedfields = | Watchedfields = | verifiedrevid = | IUPAC_name = (1''R'',3a''S'',3b''R'',5a''S'',10a''S'',10b''S'',12a''S'')-1-ethynyl-10a,12a-dimethyl-8-(methylsulfonyl)-1,2,3,3a,3b,4,5,5a,6,8,10,10a,10b,11,12,12a-hexadecahydrocyclopenta[5,6]naphtho[1,2-''f'']indazol-1-ol | image = Zanoterone.svg | image_class = skin-invert-image | width = 250px

| C=23 | H=32 | N=2 | O=3 | S=1 | smiles = C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@]2(C#C)O)CC[C@@H]4[C@@]3(CC5=CN(N=C5C4)S(=O)(=O)C)C | StdInChI_Ref = | StdInChI = 1S/C23H32N2O3S/c1-5-23(26)11-9-19-17-7-6-16-12-20-15(14-25(24-20)29(4,27)28)13-21(16,2)18(17)8-10-22(19,23)3/h1,14,16-19,26H,6-13H2,2-4H3/t16-,17+,18-,19-,21-,22-,23-/m0/s1 | StdInChIKey_Ref = | StdInChIKey = MHDDZDPNIDVLNK-ZGIWMXSJSA-N }}

'''Zanoterone''' ({{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}) (former developmental code name '''WIN-49596'''), also known as '''(5α,17α)-1'-(methylsulfonyl)-1'-H-pregn-20-yno[3,2-c]pyrazol-17-ol''',<ref name="Publishing2013">{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia, 3rd Edition|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA3517|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=3517–3518}}</ref> is a steroidal antiandrogen which was never marketed.<ref name="Morton_1999">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=mqaOMOtk61IC&pg=PA294|date=31 October 1999|publisher=Springer Science & Business Media|isbn=978-0-7514-0499-9|pages=294–}}</ref><ref name="Ganellin_1997">{{cite book| vauthors = Ganellin CR, Triggle DJ |title=Dictionary of Pharmacological Agents|url=https://books.google.com/books?id=OlP5DIq1xZkC&pg=PA540|year=1997|publisher=Taylor & Francis|isbn=978-0-412-46630-4|pages=540–}}</ref><ref name="Schröder_2009">{{cite book | vauthors = Schröder FH, Radlmaier A | chapter = Steroidal Antiandrogens | pages = 325–346 | doi = 10.1007/978-1-59259-152-7_15 | title = Hormone Therapy in Breast and Prostate Cancer | series = Cancer Drug Discovery and Development | veditors = Jordan VC, Furr BJ | year = 2009 | publisher = Humana Press | isbn = 978-1-60761-471-5}}</ref> It was investigated for the treatment of benign prostatic hyperplasia (BPH) but failed to demonstrate sufficient efficacy in phase II clinical trials, and also showed an unacceptable incidence rate and severity of side effects (e.g., breast pain and gynecomastia).<ref name="Schröder_2009" /><ref name="Wein_2011">{{cite book| vauthors = Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA |title=Campbell-Walsh Urology|url=https://books.google.com/books?id=W1aeyJD46kIC&pg=PA2637|date=28 September 2011|publisher=Elsevier Health Sciences|isbn=978-1-4557-2298-3|pages=2637–}}</ref> As such, it was not further developed.<ref name="Schröder_2009" /><ref name="Wein_2011" />

Zanoterone was derived from 5α-dihydroethisterone (5α-dihydro-17α-ethynyltestosterone).<ref name="Mallamo_1989">{{cite book | vauthors = Mallamo JP, Juniewicz PE | chapter = New horizons in the treatment of proliferative prostatic disease. |title=Annual Reports in Medicinal Chemistry| chapter-url= https://books.google.com/books?id=HrALiG-4t7UC&pg=PA200|date=8 September 1989|publisher=Academic Press|isbn=978-0-08-058368-6|pages= 197-206 (200) }}</ref><ref name="LednicerMitscher1998">{{cite book | vauthors = Lednicer D, Mitscher LA |title=The Organic Chemistry of Drug Synthesis|url=https://books.google.com/books?id=howvAQAAIAAJ|date=5 November 1998|publisher=John Wiley & Sons|isbn=978-0-471-24510-0|page=65}}</ref> It is an antagonist of the androgen receptor (K<sub>i</sub> = 2.2 μM; {{abbrlink|RBA|relative binding affinity}} compared to metribolone = 2.2%), and with the exception of antiprogestogenic activity in rat and rabbit models, is devoid of other hormonal activities.<ref name="Mallamo_1989" /><ref name="pmid2615358">{{cite journal | vauthors = Winneker RC, Wagner MM, Batzold FH | title = Studies on the mechanism of action of Win 49596: a steroidal androgen receptor antagonist | journal = Journal of Steroid Biochemistry | volume = 33 | issue = 6 | pages = 1133–1138 | date = December 1989 | pmid = 2615358 | doi = 10.1016/0022-4731(89)90420-2 }}</ref> Zanoterone does not inhibit 5α-reductase, aromatase, or 3α- or 3β-hydroxysteroid dehydrogenase ''in vitro''.<ref name="Mallamo_1989" /> The drug significantly increases testosterone and estradiol levels in men.<ref name="Berger_1995">{{cite journal | vauthors = Berger BM, Naadimuthu A, Boddy A, Fisher HA, McConnell JD, Milam D, Mobley D, Rajfer J | display-authors = 6 | title = The effect of zanoterone, a steroidal androgen receptor antagonist, in men with benign prostatic hyperplasia. The Zanoterone Study Group | journal = The Journal of Urology | volume = 154 | issue = 3 | pages = 1060–1064 | date = September 1995 | pmid = 7543598 | doi = 10.1016/S0022-5347(01)66976-3 }}</ref> Zanoterone has been found to not significantly inhibit mating performance or fertility in adult male rats at high dosages for an extended period of time.<ref name="Mallamo_1989" /> It has been found to act as an inducer of the enzyme CYP3A4 ''in vivo'' in rats.<ref name="Roberts_1996">{{cite journal | vauthors = Roberts AE, Ritz MA, Hoekstra S, Descotes G, Hincks JR | title = Induction of liver cytochrome P-450 (CYP) 3A in male and female rats by a steroidal androgen receptor antagonist, zanoterone | journal = Journal of Biochemical Toxicology | volume = 11 | issue = 3 | pages = 101–110 | year = 1996 | pmid = 9029268 | doi = 10.1002/(SICI)1522-7146(1996)11:3<101::AID-JBT1>3.0.CO;2-O }}</ref>

==Chemistry== ===Synthesis=== The chemical synthesis of zanoterone has been described.<ref>{{cite journal |author=Christiansen, R. G. |author2=Bell, M. R. |author3=D'Ambra, T. E. |author4=Mallamo, J. P. |author5=Herrmann, J. L. |author6=Ackerman, J. H. |author7=Opalka, C. J. |author8=Kullnig, R. K. |author9=Winneker, R. C. | journal=Journal of Medicinal Chemistry | title=Antiandrogenic steroidal sulfonylpyrazoles | volume=33 | issue=8 | pages=2094–2100 | date= August 1990 | url=https://pubs.acs.org/doi/abs/10.1021/jm00170a008 | doi=10.1021/jm00170a008| url-access=subscription }}</ref><ref>Robert G. Christiansen, et al. {{US patent|4684636}} (1987 to Sanofi SA).</ref>

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The Ethynylation of the keto group in Epiandrosterone [481-29-8] ('''1'''). with lithium acetylide and oxidation of the 3 hydroxy group with chromium trioxide gives 17-Ethinyl-dihydrotestosterone [13611-97-7] ('''2'''). Hydroxymethylation occurs at the C2 position upon reaction with methyl formate [107-31-3] in the presence of sodium methoxide to give PC173399331 ('''3'''). The enol alcohol is then converted to its benzoate protecting group, PC53632489 ('''4''') and reaction give Mesylhydrazide [10393-86-9] gives the pyrazole ring ('''5''').

The benzoate group was required since reacting 3 directly with the hydrazine affords mixtures of the 2 possible regioisomers.

== See also == * List of steroidal antiandrogens

== References == {{Reflist}}

Category:Abandoned drugs Category:Androstanes Category:Antiprogestogens Category:Progonadotropins Category:Pyrazoles Category:Steroidal antiandrogens Category:Sulfonamides