Steroidogenesis inhibitor

A steroidogenesis inhibitor, also known as a steroid biosynthesis inhibitor, is a type of drug which inhibits one or more of the enzymes that are involved in the process of steroidogenesis, the biosynthesis of endogenous steroids and steroid hormones.[1] They may inhibit the production of cholesterol and other sterols, sex steroids such as androgens, estrogens, and progestogens, corticosteroids such as glucocorticoids and mineralocorticoids, and neurosteroids.[1][2] They are used in the treatment of a variety of medical conditions that depend on endogenous steroids.[1]

Steroidogenesis inhibitor
Drug class
Class identifiers
SynonymsSteroid biosynthesis inhibitor; Steroid synthesis inhibitor
UseVarious
Biological targetSteroidogenic enzymes
Chemical classSteroidal; Nonsteroidal
In Wikidata

Steroidogenesis inhibitors are analogous in effect and use to antigonadotropins (which specifically inhibit gonadal sex steroid production), but work via a different mechanism of action; whereas antigonadotropins suppress gonadal production of sex steroids by effecting negative feedback on and thereby suppressing the hypothalamic–pituitary–gonadal axis, steroidogenesis inhibitors directly inhibit the enzymatic biosynthesis of steroids.[1]

Types, examples, and uses

Cholesterol synthesis inhibitors
Cholesterol biosynthesis from acetyl-CoA.

Acetyl-CoA to lanosterol inhibitors
  • Farnesyl pyrophosphate synthase (FPPS) inhibitors prevent the conversion of isopentenyl pyrophosphate (IPP) into farnesyl pyrophosphate (FPP), a mid-range step in the biosynthesis of cholesterol from acetyl-CoA, and thereby inhibit cholesterol production.[4][5] They notably do not significantly lower circulating levels of cholesterol however, and hence, unlike statins, are not suitable for the treatment of hypercholesterolemia.[6] The main examples of FPPS inhibitors are nitrogenous bisphosphonates such as alendronate, ibandronate, pamidronate, risedronate, and zoledronate, which are used in the treatment of osteoporosis.[4][5]

Lanosterol to cholesterol inhibitors
  • 7-Dehydrocholesterol reductase (7-DHCR) inhibitors such as AY-9944 and BM-15766 inhibit the production of cholesterol from 7-dehydrocholesterol, one of the last steps in cholesterol biosynthesis.[10][11] Loss-of-function mutations in the gene encoding 7-DHCR result in Smith–Lemli–Opitz syndrome (SLOS) and dramatic accumulation of 7-dehydrocholesterol.[10][11] 7-DHCR inhibitors produce an acquired form of SLOS in animals, and as such, like 24-DHCR inhibitors (see below), are probably too toxic to be used clinically.[10][11]
  • 24-Dehydrocholesterol reductase (24-DHCR) inhibitors such as azacosterol and triparanol inhibit the production of cholesterol from desmosterol, one of the last steps in cholesterol biosynthesis, and were formerly used to treat hypercholesterolemia, but were withdrawn from the market due to toxicity caused by accumulation of desmosterol in tissues.[12][13]

Steroid hormone synthesis inhibitors
Steroidogenesis, biosynthesis of steroid hormones from cholesterol.[14]

Non-specific steroid hormone synthesis inhibitors
  • 3β-Hydroxysteroid dehydrogenase (3β-HSD) inhibitors such as amphenone B,[20] azastene, cyanoketone, epostane, mitotane,[16] and trilostane inhibit the conversion of Δ5-3β-hydroxysteroids into Δ4-3-ketosteroids and thereby inhibit the production of most of the steroid hormones.[21] Due to inhibition of progesterone biosynthesis, they have been investigated as contraceptives and abortifacients (though ultimately have never been marketed for this indication),[21] and trilostane was formerly used to inhibit corticosteroid synthesis in the treatment of Cushing's syndrome.[22]

Corticosteroid-specific synthesis inhibitors

Sex steroid-specific synthesis inhibitors
  • Steroid sulfotransferase (SST) inhibitors prevent the conversion of steroid hormones such as estrone and DHEA into hormonally inactive steroid sulfates.[31] Although hormonally inactive, some steroid sulfates, such as pregnenolone sulfate and DHEA sulfate, are important neurosteroids.[32][33]

Other steroid synthesis inhibitors

List of steroid metabolism modulators
EnzymeSubstrates→ProductsInhibitorsInducers
HMG-CoA reductase
(HMGCR)		 HMG-CoA→Mevalonic acid Atorvastatin • Cerivastatin • Colestolone • Fluvastatin • Lovastatin • Mevastatin • Pitavastatin • Pravastatin • Rosuvastatin • Simvastatin
FPPS Dimethylallyl pyrophosphate (isoprenyl pyrophosphate)→Farnesyl pyrophosphate • Isopentenyl pyrophosphate→Farnesyl pyrophosphate Alendronic acid • Ibandronic acid • Incadronic acid • Pamidronic acid • Risedronic acid • Zoledronic acid
7-DHCR 7-Dehydrocholesterol→Cholesterol AY-9944 • BM-15766 • Triparanol
24-DHCR Desmosterol→Cholesterol Azacosterol • Clomifene • Triparanol • WY-3457
P450scc
(CYP11A1)		 Cholesterol→22R-Hydroxycholesterol • 22R-Hydroxycholesterol→20α,22R-Dihydroxycholesterol • 20α,22R-Dihydroxycholesterol→Pregnenolone 22-ABC • 3,3′-Dimethoxybenzidine • 3-Methoxybenzidine • Aminoglutethimide • Amphenone B • Canrenone • Cyanoketone • Danazol • Etomidate • Ketoconazole • Levoketoconazole • Mitotane • Spironolactone • Trilostane
3β-HSD
(HSD3B)		 Pregnenolone→Progesterone • 17α-Hydroxypregnenolone→17α-Hydroxyprogesterone • Dehydroepiandrosterone→Androstenedione • 5-Androstenediol→Testosterone • Androstadienol→Androstadienone 4-MA • Δ4-Abiraterone • Abiraterone • Abiraterone acetate • Amphenone B • Azastene • Cyanoketone • Cyproterone acetate • Danazol • Epostane • Genistein • Gestrinone • Medrogestone • Medroxyprogesterone acetate • Metribolone • Metyrapone • Norethisterone • Oxymetholone • Pioglitazone • Rosiglitazone • Trilostane • Troglitazone
17α-Hydroxylase,
17,20-lyase (CYP17A1)		 Pregnenolone→17α-Hydroxypregnenolone • Progesterone→17α-Hydroxyprogesterone • 17α-Hydroxypregnenolone→Dehydroepiandrosterone • 17α-Hydroxyprogesterone→Androstenedione 22-ABC • 22-Oxime • Δ4-Abiraterone • Abiraterone • Abiraterone acetate • Amphenone B • Bifluranol • Bifonazole • Canrenone • CFG-920 • Clotrimazole • Cyanoketone • Cyproterone acetate • Danazol • Econazole • Etomidate • Flutamide • Galeterone • Gestrinone • Isoconazole • Ketoconazole • L-39 • Levoketoconazole • Liarozole • LY-207,320 • MDL-27,302 • Miconazole • Mifepristone • Nilutamide • Orteronel • Pioglitazone • Prochloraz • Rosiglitazone • Seviteronel • Spironolactone • Stanozolol • SU-9055 • SU-10603 • TGF-β • Tioconazole • Troglitazone • VN/87-1 • YM116
11β-HSD
(HSD11B)		 Cortisol↔Cortisone 11-Ketoprogesterone • 11α-Hydroxyprogesterone • 11β-Hydroxyprogesterone • 18α-Glycyrrhizic acid • ABT-384 • Acetoxolone • Amphenone B • Carbenoxolone • Enoxolone (glycyrrhetinic acid) • Epigallocatechin gallate • Glycyrrhizin (glycyrrhizic acid) (licorice) • Progesterone
21-Hydroxylase
(CYP21A2)		 Progesterone→11-Deoxycorticosterone • 17α-Hydroxyprogesterone→11-Deoxycortisol Aminoglutethimide • Amphenone B • Bifonazole • Canrenone • Clotrimazole • Diazepam • Econazole • Genistein • Isoconazole • Ketoconazole • Levoketoconazole • Metyrapone • Miconazole • Midazolam • Spironolactone • Abiraterone • Abiraterone acetate • Tioconazole
11β-Hydroxylase
(CYP11B1)		 11-Deoxycorticosterone→Corticosterone • 11-Deoxycortisol→Cortisol Δ4-Abiraterone • Abiraterone • Abiraterone acetate • Aminoglutethimide • Canrenone • Etomidate • Fadrozole • FETO • Ketoconazole • Levoketoconazole • Metomidate • Metyrapol • Metyrapone • Mitotane • Potassium canrenoate • Spironolactone • Trilostane• Osilodrostat
Aldosterone
synthase (CYP11B2)		 Corticosterone→Aldosterone 18-Ethynylprogesterone (18-ethinylprogesterone) • 18-Vinylprogesterone • Aminoglutethimide • Azelnidipine • Benidipine • Canrenone • Cilnidipine • Efonidipine • FAD286 • Fadrozole • Ketoconazole • Metyrapone • Mespirenone • Osilodrostat • Potassium canrenoate • Spironolactone
17β-HSD
(HSD17B)		 Dehydroepiandrosterone↔5-Androstenediol • Androstenedione↔Testosterone • Estrone↔Estradiol Danazol • Ethanol • Fisetin • RM-532-105 • Simvastatin • STX-2171 • STX-2622 • STX-2624
5α-Reductase
(SRD5A)		 Cholestenone→5α-Cholestanone • Progesterone→5α-Dihydroprogesterone • 3α-Dihydroprogesterone→Allopregnanolone • 3β-Dihydroprogesterone→Isopregnanolone • Deoxycorticosterone→5α-Dihydrodeoxycorticosterone • Corticosterone→5α-Dihydrocorticosterone • Cortisol→5α-Dihydrocortisol • Aldosterone→5α-Dihydroaldosterone • Androstenedione→5α-Androstanedione • Testosterone→5α-Dihydrotestosterone • Androstadienone→Androstenone 22-Oxime • Δ4-Abiraterone • Abiraterone • Abiraterone acetate • Alfatradiol • Azelaic acid • β-Sitosterol • Bexlosteride • Chlormadinone acetate • Cl-4AS-1 • Dutasteride • Epitestosterone • Epristeride • Fatty acids (α-linolenic acid, linoleic acid, γ-linolenic acid, monolinolein, oleic acid) • Finasteride • Ganoderic acid • Gestodene • Izonsteride • L-39 • Lapisteride • Oxendolone • Saw palmetto extract • TFM-4AS-1 • Turosteride • Vitamin B6 • Zinc
3α-HSD
(AKR1C4)		 5α-Dihydroprogesterone↔Allopregnanolone • DHDOC↔THDOC • Dihydrotestosterone↔3α-Androstanediol Coumestrol • Daidzein • Genistein • Indometacin • Medroxyprogesterone acetate Fluoxetine • Fluvoxamine • Mirtazapine • Paroxetine • Sertraline • Venlafaxine
Aromatase
(CYP19A1)		 16α-Hydroxyandrostenedione→16α-Hydroxyestrone • Androstenedione→Estrone • Nandrolone→Estradiol • Metandienone→Methylestradiol • Methyltestosterone→Methylestradiol • Testosterone→Estradiol 4-AT • 4-Cyclohexylaniline • 4'-Hydroxynorendoxifen • 4-Hydroxytestosterone • 5α-DHNET • 20α-Dihydroprogesterone • Abyssinone II • alpha-Naphthoflavone • Aminoglutethimide • Anastrozole • Ascorbic acid (vitamin C) • Atamestane • ATD • Bifonazole • CGP-45,688 • CGS-47,645 • Chalconoids (e.g., isoliquiritigenin) • Clotrimazole • Corynesidone A • Coumestrol • DHT • Difeconazole • Econazole • Ellagitannins • Endosulfan • Exemestane • Fadrozole • Fatty acids (e.g., conjugated linoleic acid, linoleic acid, linolenic acid, palmitic acid) • Fenarimol • Finrozole • Flavonoids (e.g., 7-hydroxyflavone, 7-hydroxyflavanone, 7,8-DHF, acacetin, apigenin, baicalein, biochanin A, chrysin, EGCG, gossypetin, hesperetin, liquiritigenin, myricetin, naringenin, pinocembrin, rotenone, quercetin, sakuranetin, tectochrysin) • Formestane • Imazalil • Isoconazole • Ketoconazole • Leflutrozole • Letrozole • Liarozole • Melatonin • MEN-11066 • Miconazole • Minamestane • Nimorazole • NKS01 • Norendoxifen • ORG-33,201 • Penconazole • Phenytoin • PGE2 (dinoprostone) • Plomestane • Prochloraz • Propiconazole • Quinolinoids (e.g., berberine, casimiroin, triptoquinone A, XHN22, XHN26, XHN27) • Resorcylic acid lactones (e.g., zearalenone) • Rogletimide (pyridoglutethimide) • Stilbenoids (e.g., resveratrol) • Terpenoids (e.g., dehydroabietic acid, (–)-dehydrololiolide, retinol (vitamin A), Δ9-THC, tretinoin) • Testolactone • Tioconazole • Triadimefon • Triadimenol • Troglitazone • Valproic acid • Vorozole • Xanthones (e.g., garcinone D, garcinone E, α-mangostin, γ-mangostin, monodictyochrome A, monodictyochrome B) • YM-511 • Zinc Atrazine • Flavonoids (e.g., genistein, quercetin)
SST/EST Dehydroepiandrosterone→Dehydroepiandrosterone sulfate • Estrone→Estrone sulfate 4′OH-CB79 • 6-Hydroxyflavone • 2,6-Dichloro-4-nitrophenol (DCNP) • 7,8-Dihydroxyflavone • Equol • Galangin • Genistein • Parabens (e.g., butylparaben) • Pentachlorophenol (PCP) • Triclosan
STS Cholesterol sulfate→Cholesterol • Dehydroepiandrosterone sulfate→Dehydroepiandrosterone • Estrone sulfate→Estrone • Pregnenolone sulfate→Pregnenolone AHBS • Danazol • Estradiol sulfamate (E2MATE) • Estrone sulfamate (EMATE) • Irosustat (STX64, 667 Coumate, BN-83495) • KW-2581 • SR-16157 • STX213 • STX681 • STX1938
Sterol
27-hydroxylase
(CYP27A1)		 Cholesterol→27-Hydroxycholesterol Anastrozole • Bicalutamide • Dexmedetomidine • Fadrozole • Posaconazole • Ravuconazole
Cholesterol
7α-hydroxylase (CYP7A1)		 Cholesterol→7α-Hydroxycholesterol (intermediate to bile acids) Ketoconazole • Levoketoconazole
Lanosterol
14α-demethylase (CYP51A1)		 Lanosterol→4,4-Dimethylcholesta-8(9),14,24-trien-3β-ol (intermediate to ergosterol) Albaconazole • Aliconazole • Alteconazole • Arasertaconazole • Azaconazole • Azalanstat • Becliconazole • Bifonazole • Brolaconazole • Butoconazole • Chlormidazole • Cisconazole • Clotrimazole • Croconazole • Cyproconazole • Democonazole • Diniconazole • Doconazole • Eberconazole • Econazole • Econazole/triamcinolone • Efinaconazole • Embeconazole • Enilconazole • Etaconazole • Fenticonazole • Fluconazole • Flutrimazole • Fosfluconazole • Furconazole • Hexaconazole • Isavuconazole • Isavuconazonium chloride • Isavuconazonium sulfate • Isoconazole • Itraconazole • Ketoconazole • Lanoconazole • Levoketoconazole • Luliconazole • Miconazole • Neticonazole • Omoconazole • Orconazole • Oxiconazole • Parconazole • Penconazole • Posaconazole • Propiconazole • Pramiconazole • Quilseconazole • Ravuconazole • Saperconazole • Sertaconazole • Sulconazole • Tebuconazole • Terconazole (triaconazole) • Tioconazole • Uniconazole • Valconazole • Voriconazole • Zinoconazole • Zoficonazole


See also

References
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