Zanoterone

Last updated
Zanoterone
Zanoterone.svg
Clinical data
Other namesWIN-49596; (5α,17α)-1'-(methylsulfonyl)-1'-H-pregn-20-yno[3,2-c]pyrazol-17-ol
Routes of
administration 		By mouth
Drug class Steroidal antiandrogen
Identifiers
  • (1R,3aS,3bR,5aS,10aS,10bS,12aS)-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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C23H32N2O3S
Molar mass 416.58 g·mol−1
3D model (JSmol)
  • 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
  • InChI=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
  • Key:MHDDZDPNIDVLNK-ZGIWMXSJSA-N

Zanoterone (INN Tooltip International Nonproprietary Name, USAN Tooltip 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, [1] is a steroidal antiandrogen which was never marketed. [2] [3] [4] 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). [4] [5] As such, it was not further developed. [4] [5]

Contents

Zanoterone was derived from 5α-dihydroethisterone (5α-dihydro-17α-ethynyltestosterone). [6] [7] It is an antagonist of the androgen receptor (Ki = 2.2 μM; RBA Tooltip 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. [6] [8] Zanoterone does not inhibit 5α-reductase, aromatase, or 3α- or 3β-hydroxysteroid dehydrogenase in vitro . [6] The drug significantly increases testosterone and estradiol levels in men. [9] 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. [6] It has been found to act as an inducer of the enzyme CYP3A4 in vivo in rats. [10]

Relative potencies of selected antiandrogens
Antiandrogen Relative potency
Bicalutamide 4.3
Hydroxyflutamide 3.5
Flutamide 3.3
Cyproterone acetate 1.0
Zanoterone0.4
Description: Relative potencies of orally administered antiandrogens in antagonizing 0.8 to 1.0 mg/kg s.c. Tooltip subcutaneous injection testosterone propionate-induced ventral prostate weight increase in castrated immature male rats. Higher values mean greater potency. Sources: See template.

Chemistry

Synthesis

The chemical synthesis of zanoterone has been described. [11] [12]

Zanoterone synthesis.svg

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

References

  1. ↑ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 3517–3518. ISBN   978-0-8155-1856-3.
  2. ↑ Morton IK, Hall JM (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 294–. ISBN   978-0-7514-0499-9.
  3. ↑ Ganellin CR, Triggle DJ (1997). Dictionary of Pharmacological Agents. Taylor & Francis. pp. 540–. ISBN   978-0-412-46630-4.
  4. 1 2 3 Schröder FH, Radlmaier A (2009). "Steroidal Antiandrogens". In Jordan VC, Furr BJ (eds.). Hormone Therapy in Breast and Prostate Cancer. Cancer Drug Discovery and Development. Humana Press. pp. 325–346. doi:10.1007/978-1-59259-152-7_15. ISBN   978-1-60761-471-5.
  5. 1 2 Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA (28 September 2011). Campbell-Walsh Urology. Elsevier Health Sciences. pp. 2637–. ISBN   978-1-4557-2298-3.
  6. 1 2 3 4 Mallamo JP, Juniewicz PE (8 September 1989). "New horizons in the treatment of proliferative prostatic disease.". Annual Reports in Medicinal Chemistry. Academic Press. pp. 197-206 (200). ISBN   978-0-08-058368-6.
  7. ↑ Lednicer D, Mitscher LA (5 November 1998). The Organic Chemistry of Drug Synthesis. John Wiley & Sons. p. 65. ISBN   978-0-471-24510-0.
  8. ↑ Winneker RC, Wagner MM, Batzold FH (December 1989). "Studies on the mechanism of action of Win 49596: a steroidal androgen receptor antagonist". Journal of Steroid Biochemistry. 33 (6): 1133–1138. doi:10.1016/0022-4731(89)90420-2. PMID   2615358.
  9. ↑ Berger BM, Naadimuthu A, Boddy A, Fisher HA, McConnell JD, Milam D, et al. (September 1995). "The effect of zanoterone, a steroidal androgen receptor antagonist, in men with benign prostatic hyperplasia. The Zanoterone Study Group". The Journal of Urology. 154 (3): 1060–1064. doi:10.1016/S0022-5347(01)66976-3. PMID   7543598.
  10. ↑ Roberts AE, Ritz MA, Hoekstra S, Descotes G, Hincks JR (1996). "Induction of liver cytochrome P-450 (CYP) 3A in male and female rats by a steroidal androgen receptor antagonist, zanoterone". Journal of Biochemical Toxicology. 11 (3): 101–110. doi:10.1002/(SICI)1522-7146(1996)11:3<101::AID-JBT1>3.0.CO;2-O. PMID   9029268.
  11. ↑ Christiansen, R. G., Bell, M. R., D’Ambra, T. E., Mallamo, J. P., Herrmann, J. L., Ackerman, J. H., Opalka, C. J., Kullnig, R. K., Winneker, R. C. (August 1990). "Antiandrogenic steroidal sulfonylpyrazoles" . Journal of Medicinal Chemistry. 33 (8): 2094–2100. doi:10.1021/jm00170a008.
  12. ↑ Robert G. Christiansen, et al. U.S. patent 4,684,636 (1987 to Sanofi SA).
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