5α-Dihydroethisterone

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5α-Dihydroethisterone
5α-Dihydroethisterone.svg
Clinical data
SynonymsHE-3562; 5α-Dihydro-17α-Ethynyltestosterone; 17α-Ethynyl-DHT; 17α-Ethynyl-5α-androstan-17β-ol-3-one; 5α,17α-Pregn-20-yn-17β-ol-3-one; Ethynylandrostanolone
Drug classProgestin; Progestogen; Androgen; Anabolic steroid
Identifiers
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC21H30O2
Molar mass314.469 g/mol g·mol−1
3D model (JSmol)

5α-Dihydroethisterone (5α-DHET; developmental code name HE-3562) is an active metabolite of the formerly clinically used but now-discontinued progestin ethisterone and the experimental and never-marketed hormonal antineoplastic agent ethynylandrostanediol (HE-3235).[1][2] Its formation from its parent drugs is catalyzed by 5α-reductase in tissues that express the enzyme in high amounts like the liver, skin, hair follicles, and prostate gland.[1][2][3] 5α-DHET has significant affinity for steroid hormone receptors and may contribute importantly to the activities of its parent drugs.[1][2]

Pharmacology[edit]

Pharmacodynamics[edit]

The affinity of 5α-DHET for the androgen receptor (AR) is relatively high, in the range of 38 to 100% of that of dihydrotestosterone (DHT).[1][2][4] A study found that, similarly to norethisterone and its 5α-reduced metabolite 5α-dihydronorethisterone, 5α-DHET showed increased affinity for the AR but decreased androgenic potency relative to ethisterone (Ki = 16.1 nM for 5α-DHET and 101.1 nM for ethisterone, a 6-fold difference in affinity).[1] The decreased androgenic activity of 5α-DHET in spite of increased affinity for the AR relative to ethisterone suggests that it has comparatively reduced efficacy as an agonist of the receptor, analogously to selective androgen receptor modulators (AR partial agonists) and antiandrogens (AR antagonists).[1] 5α-DHET has relatively low affinity for the progesterone receptor, only about 12% of that of the progestogen progesterone.[2] This is significantly less than that of ethisterone, which has been found to bind to the receptor with an affinity of 35% of that of progesterone.[5][6][7] Conversely, it has relatively high affinity for the glucocorticoid receptor, about 120% of that of the corticosteroid dexamethasone.[2] In regards to the estrogen receptors, 5α-DHET has weak affinity for the ERα of about 3.5% of that of estradiol, and does not bind to the ERβ (Ki > 10 µM).[2]

In addition to steroid hormone receptors, 5α-DHET has very high affinity for sex hormone-binding globulin (Kd = 0.18 nM), an androgen and estrogen binding and transport protein that has the effect of intermittently inactivating steroid hormones (but also prolonging their half-life in the body).[8][9][10] Its affinity for this protein is among the highest of any known compound and has been found to be roughly equal to that of DHT and mesterolone (1α-methyl-DHT).[8][9][10] This property may contribute to the androgenic activity of 5α-DHET's parent drug ethisterone by displacing endogenous androgens like testosterone and DHT from SHBG.[11]

Relative affinities of ethisterone and related steroids

Compound PR AR ER GR MR SHBG CBG
Ethisterone 35 <1 <1 <1 <1 ? ?
5α-Dihydroethisterone 12 38–100a 4 120 ? 100 ?
Norethisterone 155 45 <1 3 <1 16 <1
Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the PR, testosterone (a = DHT) for the AR, E2 for the ER, DEXA for the GR, aldosterone for the MR, DHT for SHBG, and cortisol for CBG. Sources: See template.

Affinities of 5α-dihydroethisterone for steroid hormone proteins

AR ERα ERβ PR GR SHBG
IC50 RBA IC50 RBA IC50 RBA IC50 RBA IC50 RBA Kd RBA
0.5–16 nM 38–100% 229 nM 3.5% >10,000 nM IA 130 nM 12% 7 nM 120% 0.18 nM 100%
Notes: IC50 values are for binding inhibition (affinity). Reference ligands for RBA (100%) were DHT for the AR, estradiol for the ERα and ERβ, progesterone for the PR, dexamethasone for the GR, and DHT for SHBG. Sources: See template.

Pharmacokinetics[edit]

Metabolism studies of ethynylandrostanediol revealed that 5α-DHET can be metabolized via C7β and C16α hydroxylation.[2]

Chemistry[edit]

5α-DHET, also known as 5α-dihydro-17α-ethynyltestosterone (17α-ethynyl-DHT) as well as 17α-ethynyl-5α-androstan-17β-ol-3-one or 5α,17α-pregn-20-yn-17β-ol-3-one, is a synthetic androstane steroid and a derivative of testosterone.[1][2] It is specifically the combined derivative of 5α-dihydrotestosterone (DHT) and ethisterone (17α-ethynyltestosterone).[1][2] The steroid is also closely related to ethynylandrostanediol (17α-ethynyl-5α-androstane-3α,17β-diol).[2]

Analogues[edit]

Some closely related synthetic 5α-reduced steroid metabolites include 5α-dihydronandrolone, 5α-dihydronormethandrone, 5α-dihydronorethandrolone, 5α-dihydronorethisterone, and 5α-dihydrolevonorgestrel, as well as 19-norandrosterone and 19-noretiocholanolone.

Derivatives[edit]

The steroidal antiandrogen zanoterone (WIN-49596), which was investigated in the 1990s for the treatment of benign prostatic hyperplasia but was never marketed, was derived from 5α-DHET.[12][13] In terms of chemical structure, it is 5α-DHET with a pyrazole ring-containing moiety fused at the C2 and C3 positions.[14]

Synthesis[edit]

A partial synthesis of 5α-DHET from androstenedione has been published.[15]

References[edit]

  1. ^ a b c d e f g h Lemus AE, Enríquez J, García GA, Grillasca I, Pérez-Palacios G (January 1997). "5alpha-reduction of norethisterone enhances its binding affinity for androgen receptors but diminishes its androgenic potency". J. Steroid Biochem. Mol. Biol. 60 (1–2): 121–9. doi:10.1016/S0960-0760(96)00172-0. PMID 9182866.
  2. ^ a b c d e f g h i j k Ahlem C, Kennedy M, Page T, Bell D, Delorme E, Villegas S, Reading C, White S, Stickney D, Frincke J (February 2012). "17α-alkynyl 3α, 17β-androstanediol non-clinical and clinical pharmacology, pharmacokinetics and metabolism". Invest New Drugs. 30 (1): 59–78. doi:10.1007/s10637-010-9517-0. PMID 20814732.
  3. ^ Stephanie Watts; Carl Faingold; George Dunaway; Lynn Crespo (1 April 2009). Brody's Human Pharmacology - E-Book. Elsevier Health Sciences. pp. 468–. ISBN 0-323-07575-4.
  4. ^ Cunningham GR, Lobl TJ, Cockrell C, Shao TC, Tindall DJ (May 1983). "Characterization of steroid binding specificity of the androgen receptor in human foreskin fibroblasts". Steroids. 41 (5): 617–26. doi:10.1016/0039-128X(83)90027-2. PMID 6658893.
  5. ^ Ojasoo T, Raynaud JP, Doé JC (January 1994). "Affiliations among steroid receptors as revealed by multivariate analysis of steroid binding data". J. Steroid Biochem. Mol. Biol. 48 (1): 31–46. doi:10.1016/0960-0760(94)90248-8. PMID 8136304.
  6. ^ Ojasoo T, Raynaud JP (November 1978). "Unique steroid congeners for receptor studies". Cancer Res. 38 (11 Pt 2): 4186–98. PMID 359134.
  7. ^ Delettré J, Mornon JP, Lepicard G, Ojasoo T, Raynaud JP (January 1980). "Steroid flexibility and receptor specificity". J. Steroid Biochem. 13 (1): 45–59. doi:10.1016/0022-4731(80)90112-0. PMID 7382482.
  8. ^ a b Cunningham GR, Tindall DJ, Lobl TJ, Campbell JA, Means AR (September 1981). "Steroid structural requirements for high affinity binding to human sex steroid binding protein (SBP)". Steroids. 38 (3): 243–62. doi:10.1016/0039-128X(81)90061-1. PMID 7197818.
  9. ^ a b Cherkasov A, Ban F, Santos-Filho O, Thorsteinson N, Fallahi M, Hammond GL (April 2008). "An updated steroid benchmark set and its application in the discovery of novel nanomolar ligands of sex hormone-binding globulin". J. Med. Chem. 51 (7): 2047–56. doi:10.1021/jm7011485. PMID 18330978.
  10. ^ a b Nikolic K, Filipic S, Agbaba D (December 2012). "Multi-target QSAR and docking study of steroids binding to corticosteroid-binding globulin and sex hormone-binding globulin". Curr Comput Aided Drug Des. 8 (4): 296–308. doi:10.2174/157340912803519642. PMID 22242800.
  11. ^ William Llewellyn (2011). Anabolics. Molecular Nutrition Llc. pp. 641–. ISBN 978-0-9828280-1-4.
  12. ^ Annual Reports in Medicinal Chemistry. Academic Press. 8 September 1989. pp. 200–. ISBN 978-0-08-058368-6.
  13. ^ Daniel Lednicer; Lester A. Mitscher (5 November 1998). The Organic Chemistry of Drug Synthesis. John Wiley & Sons. p. 65. ISBN 978-0-471-24510-0.
  14. ^ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 3517–. ISBN 978-0-8155-1856-3.
  15. ^ Scaros, MG, Yonan, PK, Paul, K, Schulz, J; Park, FC (2001). "Novel preparation of 5α-dihydroethisterone from androst-4-ene-3,17-dione". Chemical Industries (Dekker). 82 (Catalysis of Organic Reactions): 307–313. ISSN 0737-8025