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 AtorvastatinCerivastatinColestoloneFluvastatinLovastatinMevastatinPitavastatinPravastatinRosuvastatinSimvastatin
FPPS Dimethylallyl pyrophosphate (isoprenyl pyrophosphate)→Farnesyl pyrophosphate • Isopentenyl pyrophosphate→Farnesyl pyrophosphate Alendronic acidIbandronic acidIncadronic acidPamidronic acidRisedronic acidZoledronic acid
7-DHCR 7-Dehydrocholesterol→Cholesterol AY-9944BM-15766Triparanol
24-DHCR Desmosterol→Cholesterol Azacosterol • ClomifeneTriparanolWY-3457
P450scc
(CYP11A1)
Cholesterol22R-Hydroxycholesterol22R-Hydroxycholesterol20α,22R-Dihydroxycholesterol20α,22R-DihydroxycholesterolPregnenolone 22-ABC3,3′-Dimethoxybenzidine3-MethoxybenzidineAminoglutethimideAmphenone BCanrenone • Cyanoketone • DanazolEtomidateKetoconazoleLevoketoconazoleMitotaneSpironolactoneTrilostane
3β-HSD
(HSD3B)
PregnenoloneProgesterone17α-Hydroxypregnenolone17α-HydroxyprogesteroneDehydroepiandrosteroneAndrostenedione5-AndrostenediolTestosterone • Androstadienol→Androstadienone 4-MAΔ4-AbirateroneAbirateroneAbiraterone acetateAmphenone B • Azastene • Cyanoketone • Cyproterone acetateDanazolEpostaneGenisteinGestrinoneMedrogestoneMedroxyprogesterone acetateMetriboloneMetyraponeNorethisteroneOxymetholonePioglitazoneRosiglitazoneTrilostaneTroglitazone
17α-Hydroxylase,
17,20-lyase (CYP17A1)
Pregnenolone17α-HydroxypregnenoloneProgesterone17α-Hydroxyprogesterone17α-HydroxypregnenoloneDehydroepiandrosterone17α-HydroxyprogesteroneAndrostenedione 22-ABC22-OximeΔ4-AbirateroneAbirateroneAbiraterone acetateAmphenone BBifluranolBifonazoleCanrenoneCFG-920Clotrimazole • Cyanoketone • Cyproterone acetateDanazolEconazoleEtomidateFlutamideGaleteroneGestrinoneIsoconazoleKetoconazoleL-39LevoketoconazoleLiarozoleLY-207,320MDL-27,302MiconazoleMifepristoneNilutamideOrteronelPioglitazoneProchlorazRosiglitazoneSeviteronelSpironolactoneStanozololSU-9055SU-10603 • TGF-β • TioconazoleTroglitazoneVN/87-1YM116
11β-HSD
(HSD11B)
CortisolCortisone 11-Ketoprogesterone11α-Hydroxyprogesterone11β-Hydroxyprogesterone18α-Glycyrrhizic acidABT-384AcetoxoloneAmphenone BCarbenoxoloneEnoxolone (glycyrrhetinic acid)Epigallocatechin gallate • Glycyrrhizin (glycyrrhizic acid) (licorice) • Progesterone
21-Hydroxylase
(CYP21A2)
Progesterone→11-Deoxycorticosterone • 17α-Hydroxyprogesterone11-Deoxycortisol AminoglutethimideAmphenone BBifonazoleCanrenoneClotrimazoleDiazepamEconazoleGenisteinIsoconazoleKetoconazoleLevoketoconazoleMetyraponeMiconazoleMidazolamSpironolactoneAbirateroneAbiraterone acetateTioconazole
11β-Hydroxylase
(CYP11B1)
11-Deoxycorticosterone→Corticosterone • 11-DeoxycortisolCortisol Δ4-AbirateroneAbirateroneAbiraterone acetateAminoglutethimideCanrenoneEtomidateFadrozoleFETOKetoconazoleLevoketoconazoleMetomidateMetyrapolMetyraponeMitotanePotassium canrenoateSpironolactoneTrilostaneOsilodrostat
Aldosterone
synthase (CYP11B2)
Corticosterone→Aldosterone 18-Ethynylprogesterone (18-ethinylprogesterone)18-VinylprogesteroneAminoglutethimideAzelnidipineBenidipineCanrenoneCilnidipineEfonidipineFAD286FadrozoleKetoconazoleMetyraponeMespirenoneOsilodrostatPotassium canrenoateSpironolactone
17β-HSD
(HSD17B)
Dehydroepiandrosterone5-AndrostenediolAndrostenedioneTestosteroneEstroneEstradiol DanazolEthanol • Fisetin • RM-532-105SimvastatinSTX-2171STX-2622STX-2624
5α-Reductase
(SRD5A)
Cholestenone5α-CholestanoneProgesterone→5α-Dihydroprogesterone • 3α-Dihydroprogesterone→Allopregnanolone • 3β-Dihydroprogesterone→IsopregnanoloneDeoxycorticosterone→5α-Dihydrodeoxycorticosterone • Corticosterone→5α-Dihydrocorticosterone • Cortisol→5α-Dihydrocortisol • Aldosterone→5α-Dihydroaldosterone • Androstenedione→5α-Androstanedione • Testosterone5α-Dihydrotestosterone • Androstadienone→Androstenone 22-OximeΔ4-AbirateroneAbirateroneAbiraterone acetateAlfatradiolAzelaic acidβ-SitosterolBexlosterideChlormadinone acetateCl-4AS-1DutasterideEpitestosteroneEpristeride • Fatty acids (α-linolenic acid, linoleic acid, γ-linolenic acid, monolinolein, oleic acid) • Finasteride • Ganoderic acid • GestodeneIzonsterideL-39LapisterideOxendoloneSaw palmetto extractTFM-4AS-1TurosterideVitamin B6Zinc
3α-HSD
(AKR1C4)
5α-Dihydroprogesterone↔Allopregnanolone • DHDOC↔THDOCDihydrotestosterone3α-Androstanediol Coumestrol • Daidzein • GenisteinIndometacinMedroxyprogesterone acetate FluoxetineFluvoxamineMirtazapineParoxetineSertralineVenlafaxine
Aromatase
(CYP19A1)
16α-Hydroxyandrostenedione→16α-HydroxyestroneAndrostenedioneEstroneNandroloneEstradiolMetandienoneMethylestradiolMethyltestosteroneMethylestradiolTestosteroneEstradiol 4-AT4-Cyclohexylaniline4'-Hydroxynorendoxifen4-Hydroxytestosterone5α-DHNET20α-DihydroprogesteroneAbyssinone II • alpha-Naphthoflavone • AminoglutethimideAnastrozoleAscorbic acid (vitamin C) • AtamestaneATDBifonazoleCGP-45,688CGS-47,645 • Chalconoids (e.g., isoliquiritigenin) • ClotrimazoleCorynesidone A • Coumestrol • DHTDifeconazoleEconazole • Ellagitannins • EndosulfanExemestaneFadrozole • 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 • IsoconazoleKetoconazoleLeflutrozoleLetrozoleLiarozoleMelatoninMEN-11066MiconazoleMinamestaneNimorazoleNKS01NorendoxifenORG-33,201PenconazolePhenytoinPGE2 (dinoprostone)PlomestaneProchloraz • 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) • TestolactoneTioconazole • Triadimefon • TriadimenolTroglitazoneValproic acidVorozole • Xanthones (e.g., garcinone D, garcinone E, α-mangostin, γ-mangostin, monodictyochrome A, monodictyochrome B) • YM-511Zinc Atrazine • Flavonoids (e.g., genistein, quercetin)
SST/EST DehydroepiandrosteroneDehydroepiandrosterone sulfateEstrone→Estrone sulfate 4′OH-CB79 • 6-Hydroxyflavone • 2,6-Dichloro-4-nitrophenol (DCNP)7,8-DihydroxyflavoneEquol • Galangin • Genistein • Parabens (e.g., butylparaben) • Pentachlorophenol (PCP) • Triclosan
STS Cholesterol sulfate→CholesterolDehydroepiandrosterone sulfateDehydroepiandrosterone • Estrone sulfate→EstronePregnenolone sulfatePregnenolone AHBSDanazolEstradiol sulfamate (E2MATE)Estrone sulfamate (EMATE)Irosustat (STX64, 667 Coumate, BN-83495)KW-2581SR-16157STX213STX681STX1938
Sterol
27-hydroxylase

(CYP27A1)
Cholesterol→27-Hydroxycholesterol AnastrozoleBicalutamideDexmedetomidineFadrozolePosaconazoleRavuconazole
Cholesterol
7α-hydroxylase (CYP7A1)
Cholesterol→7α-Hydroxycholesterol (intermediate to bile acids) KetoconazoleLevoketoconazole
Lanosterol
14α-demethylase (CYP51A1)
Lanosterol→4,4-Dimethylcholesta-8(9),14,24-trien-3β-ol (intermediate to ergosterol) AlbaconazoleAliconazoleAlteconazoleArasertaconazoleAzaconazoleAzalanstatBecliconazoleBifonazoleBrolaconazoleButoconazoleChlormidazoleCisconazoleClotrimazoleCroconazole • Cyproconazole • DemoconazoleDiniconazoleDoconazoleEberconazoleEconazoleEconazole/triamcinoloneEfinaconazoleEmbeconazole • Enilconazole • EtaconazoleFenticonazoleFluconazoleFlutrimazoleFosfluconazoleFurconazole • Hexaconazole • IsavuconazoleIsavuconazonium chlorideIsavuconazonium sulfateIsoconazoleItraconazoleKetoconazoleLanoconazoleLevoketoconazoleLuliconazoleMiconazoleNeticonazoleOmoconazoleOrconazoleOxiconazoleParconazolePenconazolePosaconazole • Propiconazole • PramiconazoleQuilseconazoleRavuconazoleSaperconazoleSertaconazoleSulconazole • Tebuconazole • Terconazole (triaconazole)Tioconazole • Uniconazole • ValconazoleVoriconazoleZinoconazoleZoficonazole


See also

References

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