17α-Ethynyl-3α-androstanediol
Clinical data
Other namesEthynylandrostanediol; HE3235; Apoptone; 17α-Ethynyl-5α-androstanediol; 17α-Ethynyl-5α-androstane-3α,17β-diol; 5α-Pregn-20-yne-3α,17α-diol
Routes of
administration		By mouth
Drug classEstrogen
Identifiers
  • (3R,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
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H32O2
Molar mass316.485 g·mol−1
3D model (JSmol)
  • C[C@]12CC[C@H](C[C@@H]1CC[C@@H]3[C@@H]2CC[C@]4([C@H]3CC[C@]4(C#C)O)C)O
  • 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-JRRMKBMNSA-N

17α-Ethynyl-3α-androstanediol (developmental code names HE-3235, Apoptone), also known as 17α-ethynyl-5α-androstane-3α,17β-diol, is a synthetic androstane steroid and a 17α-substituted derivative of 3α-androstanediol which was never marketed.[1][2][3] It was under development for the treatment of prostate cancer but was discontinued.[1][2][3]

17α-Ethynyl-3α-androstanediol itself shows very low affinity for steroid receptors, including the ARTooltip androgen receptor, ERαTooltip estrogen receptor alpha, ERβTooltip estrogen receptor beta, PRTooltip progesterone receptor, and GRTooltip glucocorticoid receptor, and its mechanism of action is not well-characterized.[1][4] It produces 5α-dihydroethisterone (5α-dihydro-17α-ethynyltestosterone), a ligand of several steroid hormone receptors, and 17α-ethynyl-3β-androstanediol, an estrogen, as active metabolites.[1][5] These metabolites may contribute importantly to the biological activity of 17α-ethynyl-3α-androstanediol, with 17α-ethynyl-3α-androstanediol potentially serving as a prodrug.[1][5]

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
Raloxifene–41.2 (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-164,384–63.5 (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
Coumestrol–9.225 (0.0117–94)64.125 (0.41–185)0.14–80.00.07–27.0Xenoestrogen
Genistein–0.445 (0.0012–16)33.42 (0.86–87)2.6–1260.3–12.8Xenoestrogen
Equol–0.2–0.2870.85 (0.10–2.85) ? ?Xenoestrogen
Daidzein–0.07 (0.0018–9.3)0.7865 (0.04–17.1)2.085.3Xenoestrogen
Biochanin A–0.04 (0.022–0.15)0.6225 (0.010–1.2)1748.9Xenoestrogen
Kaempferol–0.07 (0.029–0.10)2.2 (0.002–3.00) ? ?Xenoestrogen
Naringenin–0.0054 (<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
Miroestrol–0.39 ? ? ?Xenoestrogen
Deoxymiroestrol–2.0 ? ? ?Xenoestrogen
β-Sitosterol–<0.001–0.0875<0.001–0.016 ? ?Xenoestrogen
Resveratrol–<0.001–0.0032 ? ? ?Xenoestrogen
α-Zearalenol–48 (13–52.5) ? ? ?Xenoestrogen
β-Zearalenol–0.6 (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'-DDT–0.0073–0.4 ? ? ?Xenoestrogen
p,p'-DDT–0.03 ? ? ?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-Androstenediol–0.50.62319Androgen
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-Hydroxytibolone–2.5 (1.06–5.0)0.6–0.8 ? ?Progestogen
3β-Hydroxytibolone–1.6 (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-3α-androstanediol include 17α-ethynyl-3β-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. 1 2 3 4 5 Ahlem C, Kennedy M, Page T, Bell D, Delorme E, Villegas S, Reading C, White S, Stickney D, Frincke J (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.
  2. 1 2 Trauger R, Corey E, Bell D, White S, Garsd A, Stickney D, Reading C, Frincke J (2009). "Inhibition of androstenediol-dependent LNCaP tumour growth by 17alpha-ethynyl-5alpha-androstane-3alpha, 17beta-diol (HE3235)". Br. J. Cancer. 100 (7): 1068–72. doi:10.1038/sj.bjc.6604987. PMC 2669987. PMID 19337256.
  3. 1 2 http://webcache.googleusercontent.com/search?q=cache:Jy1DYIHEUtQJ:adisinsight.springer.com/drugs/800025305%5B%5D
  4. ↑ Koreckij TD, Trauger RJ, Montgomery RB, Pitts TE, Coleman I, Nguyen H, Reading CL, Nelson PS, Vessella RL, Corey E (2009). "HE3235 inhibits growth of castration-resistant prostate cancer". Neoplasia. 11 (11): 1216–25. doi:10.1593/neo.09960. PMC 2767223. PMID 19881957.
  5. 1 2 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.


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