17α-Ethynyl-3β-androstanediol

17α-Ethynyl-3β-androstanediol (developmental code HE-3539; also known as 17α-ethynyl-5α-androstane-3β,17β-diol) is a synthetic estrogen and a 17α-substituted derivative of 3β-androstanediol which was never marketed.[1][2]

17α-Ethynyl-3β-androstanediol
Clinical data
Other namesHE-3539; HE3539; Ethinylandrostanediol; 17α-Ethynyl-5α-androstane-3β,17β-diol; 5α,17α-Pregn-20-yne-3β,17-diol
Routes of
administration
By mouth
Drug classEstrogen
Identifiers
IUPAC name
  • (5S,8R,9S,10S,13S,14S,17R)-17-ethynyl-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,14,15,16-tetradecahydrocyclopenta[a]phenanthrene-3,17-diol
CAS Number
PubChem CID
Chemical and physical data
FormulaC21H32O2
Molar mass316.485 g·mol−1
3D model (JSmol)
SMILES
  • C[C@]12CCC(C[C@@H]1CC[C@@H]3[C@@H]2CC[C@]4([C@H]3CC[C@]4(C#C)O)C)O
InChI
  • InChI=1S/C21H32O2/c1-4-21(23)12-9-18-16-6-5-14-13-15(22)7-10-19(14,2)17(16)8-11-20(18,21)3/h1,14-18,22-23H,5-13H2,2-3H3/t14-,15?,16+,17-,18-,19-,20-,21-/m0/s1
  • Key:CKAXZOYFIHQCBN-KVECEQEYSA-N

17α-Ethynyl-3β-androstanediol shows high affinity for the estrogen receptors in vitro (IC50 values of 16 nM for ERα and 126 nM for ERβ relative to values of 8 nM at ERα and 7 nM at ERβ for estradiol), and activates the estrogen receptors in vitro (EC50 value of 0.9 nM relative to 0.002 nM for estradiol).[2] It also has weak affinity for the androgen receptor in vitro (IC50 = 277 nM relative to 15 nM for dihydrotestosterone), but doesn't appear to activate the receptor.[2] 17α-Ethynyl-3β-androstanediol may produce 17α-ethynyl-3α-androstanediol and 5α-dihydroethisterone (5α-dihydro-17α-ethynyltestosterone) as active metabolites in vivo.[2] In accordance with its in-vitro estrogenic activity, 17α-ethynyl-3β-androstanediol produces estrogenic effects like uterotrophy and testicular atrophy in animals.[1]

Esters of 17α-ethynyl-3β-androstanediol have been developed and studied.[3]

17α-Ethynyl-3β-androstanediol is a positional isomer of 17α-ethynyl-3α-androstanediol, and is a metabolite of this compound in vivo via metabolic inversion of the position of the C3 hydroxyl group.[2] It may be involved in the biological activity of 17α-ethynyl-3α-androstanediol.[2]

Affinities of estrogen receptor ligands for the ERα and ERβ
LigandOther namesRelative binding affinities (RBA, %)aAbsolute binding affinities (Ki, nM)aAction
ERαERβERαERβ
EstradiolE2; 17β-Estradiol1001000.115 (0.04–0.24)0.15 (0.10–2.08)Estrogen
EstroneE1; 17-Ketoestradiol16.39 (0.7–60)6.5 (1.36–52)0.445 (0.3–1.01)1.75 (0.35–9.24)Estrogen
EstriolE3; 16α-OH-17β-E212.65 (4.03–56)26 (14.0–44.6)0.45 (0.35–1.4)0.7 (0.63–0.7)Estrogen
EstetrolE4; 15α,16α-Di-OH-17β-E24.03.04.919Estrogen
Alfatradiol17α-Estradiol20.5 (7–80.1)8.195 (2–42)0.2–0.520.43–1.2Metabolite
16-Epiestriol16β-Hydroxy-17β-estradiol7.795 (4.94–63)50 ? ?Metabolite
17-Epiestriol16α-Hydroxy-17α-estradiol55.45 (29–103)79–80 ? ?Metabolite
16,17-Epiestriol16β-Hydroxy-17α-estradiol1.013 ? ?Metabolite
2-Hydroxyestradiol2-OH-E222 (7–81)11–352.51.3Metabolite
2-Methoxyestradiol2-MeO-E20.0027–2.01.0 ? ?Metabolite
4-Hydroxyestradiol4-OH-E213 (8–70)7–561.01.9Metabolite
4-Methoxyestradiol4-MeO-E22.01.0 ? ?Metabolite
2-Hydroxyestrone2-OH-E12.0–4.00.2–0.4 ? ?Metabolite
2-Methoxyestrone2-MeO-E1<0.001–<1<1 ? ?Metabolite
4-Hydroxyestrone4-OH-E11.0–2.01.0 ? ?Metabolite
4-Methoxyestrone4-MeO-E1<1<1 ? ?Metabolite
16α-Hydroxyestrone16α-OH-E1; 17-Ketoestriol2.0–6.535 ? ?Metabolite
2-Hydroxyestriol2-OH-E32.01.0 ? ?Metabolite
4-Methoxyestriol4-MeO-E31.01.0 ? ?Metabolite
Estradiol sulfateE2S; Estradiol 3-sulfate<1<1 ? ?Metabolite
Estradiol disulfateEstradiol 3,17β-disulfate0.0004 ? ? ?Metabolite
Estradiol 3-glucuronideE2-3G0.0079 ? ? ?Metabolite
Estradiol 17β-glucuronideE2-17G0.0015 ? ? ?Metabolite
Estradiol 3-gluc. 17β-sulfateE2-3G-17S0.0001 ? ? ?Metabolite
Estrone sulfateE1S; Estrone 3-sulfate<1<1>10>10Metabolite
Estradiol benzoateEB; Estradiol 3-benzoate10 ? ? ?Estrogen
Estradiol 17β-benzoateE2-17B11.332.6 ? ?Estrogen
Estrone methyl etherEstrone 3-methyl ether0.145 ? ? ?Estrogen
ent-Estradiol1-Estradiol1.31–12.349.44–80.07 ? ?Estrogen
Equilin7-Dehydroestrone13 (4.0–28.9)13.0–490.790.36Estrogen
Equilenin6,8-Didehydroestrone2.0–157.0–200.640.62Estrogen
17β-Dihydroequilin7-Dehydro-17β-estradiol7.9–1137.9–1080.090.17Estrogen
17α-Dihydroequilin7-Dehydro-17α-estradiol18.6 (18–41)14–320.240.57Estrogen
17β-Dihydroequilenin6,8-Didehydro-17β-estradiol35–6890–1000.150.20Estrogen
17α-Dihydroequilenin6,8-Didehydro-17α-estradiol20490.500.37Estrogen
Δ8-Estradiol8,9-Dehydro-17β-estradiol68720.150.25Estrogen
Δ8-Estrone8,9-Dehydroestrone19320.520.57Estrogen
EthinylestradiolEE; 17α-Ethynyl-17β-E2120.9 (68.8–480)44.4 (2.0–144)0.02–0.050.29–0.81Estrogen
MestranolEE 3-methyl ether ?2.5 ? ?Estrogen
MoxestrolRU-2858; 11β-Methoxy-EE35–435–200.52.6Estrogen
Methylestradiol17α-Methyl-17β-estradiol7044 ? ?Estrogen
DiethylstilbestrolDES; Stilbestrol129.5 (89.1–468)219.63 (61.2–295)0.040.05Estrogen
HexestrolDihydrodiethylstilbestrol153.6 (31–302)60–2340.060.06Estrogen
DienestrolDehydrostilbestrol37 (20.4–223)56–4040.050.03Estrogen
Benzestrol (B2)114 ? ? ?Estrogen
ChlorotrianiseneTACE1.74 ?15.30 ?Estrogen
TriphenylethyleneTPE0.074 ? ? ?Estrogen
TriphenylbromoethyleneTPBE2.69 ? ? ?Estrogen
TamoxifenICI-46,4743 (0.1–47)3.33 (0.28–6)3.4–9.692.5SERM
Afimoxifene4-Hydroxytamoxifen; 4-OHT100.1 (1.7–257)10 (0.98–339)2.3 (0.1–3.61)0.04–4.8SERM
Toremifene4-Chlorotamoxifen; 4-CT ? ?7.14–20.315.4SERM
ClomifeneMRL-4125 (19.2–37.2)120.91.2SERM
CyclofenilF-6066; Sexovid151–152243 ? ?SERM
NafoxidineU-11,000A30.9–44160.30.8SERM
Raloxifene41.2 (7.8–69)5.34 (0.54–16)0.188–0.5220.2SERM
ArzoxifeneLY-353,381 ? ?0.179 ?SERM
LasofoxifeneCP-336,15610.2–16619.00.229 ?SERM
OrmeloxifeneCentchroman ? ?0.313 ?SERM
Levormeloxifene6720-CDRI; NNC-460,0201.551.88 ? ?SERM
OspemifeneDeaminohydroxytoremifene0.82–2.630.59–1.22 ? ?SERM
Bazedoxifene ? ?0.053 ?SERM
EtacstilGW-56384.3011.5 ? ?SERM
ICI-164,38463.5 (3.70–97.7)1660.20.08Antiestrogen
FulvestrantICI-182,78043.5 (9.4–325)21.65 (2.05–40.5)0.421.3Antiestrogen
PropylpyrazoletriolPPT49 (10.0–89.1)0.120.4092.8ERα agonist
16α-LE216α-Lactone-17β-estradiol14.6–570.0890.27131ERα agonist
16α-Iodo-E216α-Iodo-17β-estradiol30.22.30 ? ?ERα agonist
MethylpiperidinopyrazoleMPP110.05 ? ?ERα antagonist
DiarylpropionitrileDPN0.12–0.256.6–1832.41.7ERβ agonist
8β-VE28β-Vinyl-17β-estradiol0.3522.0–8312.90.50ERβ agonist
PrinaberelERB-041; WAY-202,0410.2767–72 ? ?ERβ agonist
ERB-196WAY-202,196 ?180 ? ?ERβ agonist
ErteberelSERBA-1; LY-500,307 ? ?2.680.19ERβ agonist
SERBA-2 ? ?14.51.54ERβ agonist
Coumestrol9.225 (0.0117–94)64.125 (0.41–185)0.14–80.00.07–27.0Xenoestrogen
Genistein0.445 (0.0012–16)33.42 (0.86–87)2.6–1260.3–12.8Xenoestrogen
Equol0.2–0.2870.85 (0.10–2.85) ? ?Xenoestrogen
Daidzein0.07 (0.0018–9.3)0.7865 (0.04–17.1)2.085.3Xenoestrogen
Biochanin A0.04 (0.022–0.15)0.6225 (0.010–1.2)1748.9Xenoestrogen
Kaempferol0.07 (0.029–0.10)2.2 (0.002–3.00) ? ?Xenoestrogen
Naringenin0.0054 (<0.001–0.01)0.15 (0.11–0.33) ? ?Xenoestrogen
8-Prenylnaringenin8-PN4.4 ? ? ?Xenoestrogen
Quercetin<0.001–0.010.002–0.040 ? ?Xenoestrogen
Ipriflavone<0.01<0.01 ? ?Xenoestrogen
Miroestrol0.39 ? ? ?Xenoestrogen
Deoxymiroestrol2.0 ? ? ?Xenoestrogen
β-Sitosterol<0.001–0.0875<0.001–0.016 ? ?Xenoestrogen
Resveratrol<0.001–0.0032 ? ? ?Xenoestrogen
α-Zearalenol48 (13–52.5) ? ? ?Xenoestrogen
β-Zearalenol0.6 (0.032–13) ? ? ?Xenoestrogen
Zeranolα-Zearalanol48–111 ? ? ?Xenoestrogen
Taleranolβ-Zearalanol16 (13–17.8)140.80.9Xenoestrogen
ZearalenoneZEN7.68 (2.04–28)9.45 (2.43–31.5) ? ?Xenoestrogen
ZearalanoneZAN0.51 ? ? ?Xenoestrogen
Bisphenol ABPA0.0315 (0.008–1.0)0.135 (0.002–4.23)19535Xenoestrogen
EndosulfanEDS<0.001–<0.01<0.01 ? ?Xenoestrogen
KeponeChlordecone0.0069–0.2 ? ? ?Xenoestrogen
o,p'-DDT0.0073–0.4 ? ? ?Xenoestrogen
p,p'-DDT0.03 ? ? ?Xenoestrogen
Methoxychlorp,p'-Dimethoxy-DDT0.01 (<0.001–0.02)0.01–0.13 ? ?Xenoestrogen
HPTEHydroxychlor; p,p'-OH-DDT1.2–1.7 ? ? ?Xenoestrogen
TestosteroneT; 4-Androstenolone<0.0001–<0.01<0.002–0.040>5000>5000Androgen
DihydrotestosteroneDHT; 5α-Androstanolone0.01 (<0.001–0.05)0.0059–0.17221–>500073–1688Androgen
Nandrolone19-Nortestosterone; 19-NT0.010.2376553Androgen
DehydroepiandrosteroneDHEA; Prasterone0.038 (<0.001–0.04)0.019–0.07245–1053163–515Androgen
5-AndrostenediolA5; Androstenediol6173.60.9Androgen
4-Androstenediol0.50.62319Androgen
4-AndrostenedioneA4; Androstenedione<0.01<0.01>10000>10000Androgen
3α-Androstanediol3α-Adiol0.070.326048Androgen
3β-Androstanediol3β-Adiol3762Androgen
Androstanedione5α-Androstanedione<0.01<0.01>10000>10000Androgen
Etiocholanedione5β-Androstanedione<0.01<0.01>10000>10000Androgen
Methyltestosterone17α-Methyltestosterone<0.0001 ? ? ?Androgen
Ethinyl-3α-androstanediol17α-Ethynyl-3α-adiol4.0<0.07 ? ?Estrogen
Ethinyl-3β-androstanediol17α-Ethynyl-3β-adiol505.6 ? ?Estrogen
ProgesteroneP4; 4-Pregnenedione<0.001–0.6<0.001–0.010 ? ?Progestogen
NorethisteroneNET; 17α-Ethynyl-19-NT0.085 (0.0015–<0.1)0.1 (0.01–0.3)1521084Progestogen
Norethynodrel5(10)-Norethisterone0.5 (0.3–0.7)<0.1–0.221453Progestogen
Tibolone7α-Methylnorethynodrel0.5 (0.45–2.0)0.2–0.076 ? ?Progestogen
Δ4-Tibolone7α-Methylnorethisterone0.069–<0.10.027–<0.1 ? ?Progestogen
3α-Hydroxytibolone2.5 (1.06–5.0)0.6–0.8 ? ?Progestogen
3β-Hydroxytibolone1.6 (0.75–1.9)0.070–0.1 ? ?Progestogen
Footnotes: a = (1) Binding affinity values are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. The full sets of values within the ranges can be found in the Wiki code. (2) Binding affinities were determined via displacement studies in a variety of in-vitro systems with labeled estradiol and human ERα and ERβ proteins (except the ERβ values from Kuiper et al. (1997), which are rat ERβ). Sources: See template page.

Analogues of 17α-ethynyl-3β-androstanediol include 17α-ethynyl-3α-androstanediol, ethinylandrostenediol (17α-ethynyl-5-androstenediol), ethandrostate (17α-ethynyl-5-androstenediol 3β-cyclohexanepropionate), ethinylestradiol (17α-ethynylestradiol), ethisterone (17α-ethynyltestosterone), and 5α-dihydroethisterone (17α-ethynyldihydrotestosterone).

References

  1. Beyler AL, Clinton RO (June 1956). "Uterine growth stimulating and testicular growth suppressing activities of 17alpha-ethinylandrostane-3beta, 17beta-diol, its delta 5-analog and derivatives". Proc. Soc. Exp. Biol. Med. 92 (2): 404–8. doi:10.3181/00379727-92-22493. PMID 13350363. S2CID 87469965.
  2. 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. S2CID 24785562.
  3. Clinton, R.; Neumann, H.; Laskowski, S.; Christiansen, R. (1957). "Notes - Esters of 17α-Ethinyl-androstane-3β,17β-diol and 17 α-Ethinylandrost-5-ene-3β, 17β-diol". The Journal of Organic Chemistry. 22 (4): 473–475. doi:10.1021/jo01355a627. ISSN 0022-3263.



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