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Chemical compound
5α あるふぁ -Dihydroethisterone Other names HE-3562; 5α あるふぁ -Dihydro-17α あるふぁ -Ethynyltestosterone; 17α あるふぁ -Ethynyl-DHT; 17α あるふぁ -Ethynyl-5α あるふぁ -androstan-17β べーた -ol-3-one; 5α あるふぁ ,17α あるふぁ -Pregn-20-yn-17β べーた -ol-3-one; Ethynylandrostanolone Drug class Progestin ; Progestogen ; Androgen ; Anabolic steroid
(5S ,8R ,9S ,10S ,13S ,14S ,17R )-17-ethynyl-17-hydroxy-10,13-dimethyl-2,4,5,6,7,8,9,11,12,14,15,16-dodecahydro-1H -cyclopenta[a ]phenanthren-3-one
CAS Number PubChem CID ChemSpider ChEMBL Formula C 21 H 30 O 2 Molar mass 314.469 g·mol−1 3D model (JSmol )
C[C@]12CCC(=O)C[C@@H]1CC[C@@H]3[C@@H]2CC[C@]4([C@H]3CC[C@]4(C#C)O)C
InChI=1S/C21H30O2/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/h1,14,16-18,23H,5-13H2,2-3H3/t14-,16+,17-,18-,19-,20-,21-/m0/s1
Key:PVHMKHVQVIUQIP-JJFNZWTKSA-N
5α あるふぁ -Dihydroethisterone (5α あるふぁ -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 あるふぁ -reductase in tissues that express the enzyme in high amounts like the liver , skin , hair follicles , and prostate gland .[ 1] [ 2] [ 3] 5α あるふぁ -DHET has significant affinity for steroid hormone receptors and may contribute importantly to the activities of its parent drugs.[ 1] [ 2]
The affinity of 5α あるふぁ -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 あるふぁ -reduced metabolite 5α あるふぁ -dihydronorethisterone , 5α あるふぁ -DHET showed increased affinity for the AR but decreased androgenic potency relative to ethisterone (Ki = 16.1 nM for 5α あるふぁ -DHET and 101.1 nM for ethisterone, a 6-fold difference in affinity).[ 1] The decreased androgenic activity of 5α あるふぁ -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 あるふぁ -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 あるふぁ -DHET has weak affinity for the ERα あるふぁ of about 3.5% of that of estradiol , and does not bind to the ERβ べーた (Ki > 10 μ みゅー M).[ 2]
In addition to steroid hormone receptors, 5α あるふぁ -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 あるふぁ -methyl-DHT).[ 8] [ 9] [ 10] This property may contribute to the androgenic activity of 5α あるふぁ -DHET's parent drug ethisterone by displacing endogenous androgens like testosterone and DHT from SHBG.[ 11]
Metabolism studies of ethynylandrostanediol revealed that 5α あるふぁ -DHET can be metabolized via C7β べーた and C16α あるふぁ hydroxylation .[ 2]
5α あるふぁ -DHET, also known as 5α あるふぁ -dihydro-17α あるふぁ -ethynyltestosterone (17α あるふぁ -ethynyl-DHT) as well as 17α あるふぁ -ethynyl-5α あるふぁ -androstan-17β べーた -ol-3-one or 5α あるふぁ ,17α あるふぁ -pregn-20-yn-17β べーた -ol-3-one, is a synthetic androstane steroid and a derivative of testosterone .[ 1] [ 2] It is specifically the combined derivative of 5α あるふぁ -dihydrotestosterone (DHT) and ethisterone (17α あるふぁ -ethynyltestosterone).[ 1] [ 2] The steroid is also closely related to ethynylandrostanediol (17α あるふぁ -ethynyl-5α あるふぁ -androstane-3α あるふぁ ,17β べーた -diol).[ 2]
Some closely related synthetic 5α あるふぁ -reduced steroid metabolites include 5α あるふぁ -dihydronandrolone , 5α あるふぁ -dihydronormethandrone , 5α あるふぁ -dihydronorethandrolone , 5α あるふぁ -dihydronorethisterone , and 5α あるふぁ -dihydrolevonorgestrel , as well as 19-norandrosterone and 19-noretiocholanolone .
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 あるふぁ -DHET.[ 12] [ 13] In terms of chemical structure , it is 5α あるふぁ -DHET with a pyrazole ring -containing moiety fused at the C2 and C3 positions.[ 14]
A partial synthesis of 5α あるふぁ -DHET from androstenedione has been published.[ 15]
^ 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 . S2CID 33771349 .
^ 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 あるふぁ -alkynyl 3α あるふぁ , 17β べーた -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 .
^ Dunaway G (1 April 2009). "Androgens and Antiandrogens" . In Watts S, Faingold C, Dunaway G, Crespo L (eds.). Brody's Human Pharmacology - E-Book . Elsevier Health Sciences. pp. 468–. ISBN 978-0-323-07575-6 .
^ 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 . S2CID 9932822 .
^ 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 . S2CID 21336380 .
^ Ojasoo T, Raynaud JP (November 1978). "Unique steroid congeners for receptor studies" . Cancer Res . 38 (11 Pt 2): 4186–98. PMID 359134 .
^ 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 .
^ 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 . S2CID 2702353 .
^ 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 .
^ 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 .
^ Llewellyn W (2011). Anabolics . Molecular Nutrition Llc. pp. 641–. ISBN 978-0-9828280-1-4 .
^ Mallamo JP, Juniewicz PE (8 September 1989). "New Horizons in the Treatment of Proliferative Prostatic Disease" . In Johns WF (ed.). Annual Reports in Medicinal Chemistry . Vol. 24. Academic Press. pp. 200–. doi :10.1016/S0065-7743(08)60543-6 . ISBN 978-0-08-058368-6 .
^ Lednicer D, Mitscher LA (5 November 1998). The Organic Chemistry of Drug Synthesis . John Wiley & Sons. p. 65. ISBN 978-0-471-24510-0 .
^ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia (3rd ed.). Elsevier. pp. 3517–. ISBN 978-0-8155-1856-3 .
^ Scaros MG, Yonan PK, Paul K, Schulz J, Park JC (2001). "Novel preparation of 5α あるふぁ -dihydroethisterone from androst-4-ene-3,17-dione.". Chemical Industries . Vol. 82 (Catalysis of Organic Reactions). Dekker. pp. 307–313. ISSN 0737-8025 .
AR Tooltip Androgen receptor
Agonists SARMs Tooltip Selective androgen receptor modulator Antagonists
GPRC6A
ER Tooltip Estrogen receptor
Agonists
Steroidal: 2-Hydroxyestradiol
2-Hydroxyestrone
3-Methyl-19-methyleneandrosta-3,5-dien-17β べーた -ol
3α あるふぁ -Androstanediol
3α あるふぁ ,5α あるふぁ -Dihydrolevonorgestrel
3β べーた ,5α あるふぁ -Dihydrolevonorgestrel
3α あるふぁ -Hydroxytibolone
3β べーた -Hydroxytibolone
3β べーた -Androstanediol
4-Androstenediol
4-Androstenedione
4-Fluoroestradiol
4-Hydroxyestradiol
4-Hydroxyestrone
4-Methoxyestradiol
4-Methoxyestrone
5-Androstenediol
7-Oxo-DHEA
7α あるふぁ -Hydroxy-DHEA
7α あるふぁ -Methylestradiol
7β べーた -Hydroxyepiandrosterone
8,9-Dehydroestradiol
8,9-Dehydroestrone
8β べーた -VE2
10β べーた ,17β べーた -Dihydroxyestra-1,4-dien-3-one (DHED)
11β べーた -Chloromethylestradiol
11β べーた -Methoxyestradiol
15α あるふぁ -Hydroxyestradiol
16-Ketoestradiol
16-Ketoestrone
16α あるふぁ -Fluoroestradiol
16α あるふぁ -Hydroxy-DHEA
16α あるふぁ -Hydroxyestrone
16α あるふぁ -Iodoestradiol
16α あるふぁ -LE2
16β べーた -Hydroxyestrone
16β べーた ,17α あるふぁ -Epiestriol (16β べーた -hydroxy-17α あるふぁ -estradiol)
17α あるふぁ -Estradiol (alfatradiol )
17α あるふぁ -Dihydroequilenin
17α あるふぁ -Dihydroequilin
17α あるふぁ -Epiestriol (16α あるふぁ -hydroxy-17α あるふぁ -estradiol)
17α あるふぁ -Ethynyl-3α あるふぁ -androstanediol
17α あるふぁ -Ethynyl-3β べーた -androstanediol
17β べーた -Dihydroequilenin
17β べーた -Dihydroequilin
17β べーた -Methyl-17α あるふぁ -dihydroequilenin
Abiraterone
Abiraterone acetate
Alestramustine
Almestrone
Anabolic steroids (e.g., testosterone and esters , methyltestosterone , metandienone (methandrostenolone) , nandrolone and esters , many others; via estrogenic metabolites)
Atrimustine
Bolandiol
Bolandiol dipropionate
Butolame
Clomestrone
Cloxestradiol
Conjugated estriol
Conjugated estrogens
Cyclodiol
Cyclotriol
DHEA
DHEA-S
ent -Estradiol
Epiestriol (16β べーた -epiestriol, 16β べーた -hydroxy-17β べーた -estradiol)
Epimestrol
Equilenin
Equilin
ERA-63 (ORG-37663)
Esterified estrogens
Estetrol
Estradiol
Estramustine
Estramustine phosphate
Estrapronicate
Estrazinol
Estriol
Estrofurate
Estrogenic substances
Estromustine
Estrone
Etamestrol (eptamestrol)
Ethinylandrostenediol
Ethinylestradiol
Ethinylestriol
Ethylestradiol
Etynodiol
Etynodiol diacetate
Hexolame
Hippulin
Hydroxyestrone diacetate
Lynestrenol
Lynestrenol phenylpropionate
Mestranol
Methylestradiol
Moxestrol
Mytatrienediol
Nilestriol
Norethisterone
Noretynodrel
Orestrate
Pentolame
Prodiame
Prolame
Promestriene
RU-16117
Quinestradol
Quinestrol
Tibolone
Xenoestrogens: Anise -related (e.g., anethole , anol , dianethole , dianol , photoanethole )
Chalconoids (e.g., isoliquiritigenin , phloretin , phlorizin (phloridzin) , wedelolactone )
Coumestans (e.g., coumestrol , psoralidin )
Flavonoids (incl. 7,8-DHF , 8-prenylnaringenin , apigenin , baicalein , baicalin , biochanin A , calycosin , catechin , daidzein , daidzin , ECG , EGCG , epicatechin , equol , formononetin , glabrene , glabridin , genistein , genistin , glycitein , kaempferol , liquiritigenin , mirificin , myricetin , naringenin , penduletin , pinocembrin , prunetin , puerarin , quercetin , tectoridin , tectorigenin )
Lavender oil
Lignans (e.g., enterodiol , enterolactone , nyasol (cis -hinokiresinol) )
Metalloestrogens (e.g., cadmium )
Pesticides (e.g., alternariol , dieldrin , endosulfan , fenarimol , HPTE , methiocarb , methoxychlor , triclocarban , triclosan )
Phytosteroids (e.g., digitoxin (digitalis ), diosgenin , guggulsterone )
Phytosterols (e.g., β べーた -sitosterol , campesterol , stigmasterol )
Resorcylic acid lactones (e.g., zearalanone , α あるふぁ -zearalenol , β べーた -zearalenol , zearalenone , zeranol (α あるふぁ -zearalanol) , taleranol (teranol, β べーた -zearalanol) )
Steroid -like (e.g., deoxymiroestrol , miroestrol )
Stilbenoids (e.g., resveratrol , rhaponticin )
Synthetic xenoestrogens (e.g., alkylphenols , bisphenols (e.g., BPA , BPF , BPS ), DDT , parabens , PBBs , PHBA , phthalates , PCBs )
Others (e.g., agnuside , rotundifuran )
Mixed (SERMs Tooltip Selective estrogen receptor modulators ) Antagonists
Coregulator-binding modulators: ERX-11
GPER Tooltip G protein-coupled estrogen receptor
Agonists Antagonists Unknown
GR Tooltip Glucocorticoid receptor
PR Tooltip Progesterone receptor
Agonists
Testosterone derivatives: Progestins: 6,6-Difluoronorethisterone
6,6-Difluoronorethisterone acetate
17α あるふぁ -Allyl-19-nortestosterone
Allylestrenol
Altrenogest
Chloroethynylnorgestrel
Cingestol
Danazol
Desogestrel
Dienogest
Ethinylandrostenediol
Ethisterone
Ethynerone
Etonogestrel
Etynodiol
Etynodiol diacetate
Gestodene
Gestrinone
Levonorgestrel
Levonorgestrel esters (e.g., levonorgestrel butanoate )
Lynestrenol
Lynestrenol phenylpropionate
Metynodiol
Metynodiol diacetate
Norelgestromin
Norethisterone (norethindrone)
Norethisterone esters (e.g., norethisterone acetate , norethisterone enanthate )
Noretynodrel
Norgesterone
Norgestimate
Norgestrel
Norgestrienone
Norvinisterone
Oxendolone
Quingestanol
Quingestanol acetate
Tibolone
Tigestol
Tosagestin ; Anabolic–androgenic steroids: 11β べーた -Methyl-19-nortestosterone
11β べーた -Methyl-19-nortestosterone dodecylcarbonate
19-Nor-5-androstenediol
19-Nor-5-androstenedione
19-Nordehydroepiandrosterone
Bolandiol
Bolandiol dipropionate
Bolandione
Dimethisterone
Dienedione
Dienolone
Dimethandrolone
Dimethandrolone buciclate
Dimethandrolone dodecylcarbonate
Dimethandrolone undecanoate
Dimethyldienolone
Dimethyltrienolone
Ethyldienolone
Ethylestrenol (ethylnandrol)
Methyldienolone
Metribolone (R-1881)
Methoxydienone (methoxygonadiene)
Mibolerone
Nandrolone
Nandrolone esters (e.g., nandrolone decanoate , nandrolone phenylpropionate )
Norethandrolone
Normethandrone (methylestrenolone, normethandrolone, normethisterone)
RU-2309
Tetrahydrogestrinone
Trenbolone (trienolone)
Trenbolone esters (e.g., trenbolone acetate , trenbolone enanthate )
Trendione
Trestolone
Trestolone acetate
Mixed (SPRMs Tooltip Selective progesterone receptor modulators ) Antagonists
mPR Tooltip Membrane progesterone receptor (PAQR Tooltip Progestin and adipoQ receptor )