5-alpha-reductase inhibitor

5-reductase inhibitors (5-ARIs) are a class of drugswith antiandrogen eects, used primarily in the treatmentof benign prostatic hyperplasia (BPH) and androgenicalopecia.These agents inhibit the enzyme 5-reductase, whichis involved in the metabolic transformations of a vari-ety of endogenous steroids. 5-reductase inhibition ismost known for preventing conversion of testosterone,the major androgen sex hormone, to the more potentdihydrotestosterone (DHT), in androgen-associated dis-orders.

1 Medical use

Propecia (nasteride) 1 mg tablets

5-ARIs are clinically used in the treatment of conditionsthat are exacerbated by DHT:[1]

Mild-to-moderate benign prostatic hyperplasia andlower urinary tract symptoms

Androgenic alopecia in both men and women

They have also been explored in the treatment and pre-vention of prostate cancer. However, their use for this in-dication is controversial, as some authors have expressedconcern that they may inadvertently lead to developmentof more aggressive tumor variants.5-ARIs are also sometimes employed as supplementaryantiandrogens in hormone replacement therapy for transwomen.

Avodart (dutasteride) 500 g capsules

2 Adverse reactionsIn general, adverse drug reactions (ADRs) experiencedwith 5-ARIs are dose-dependent. Common ADRs in-clude impotence, decreased libido, decreased ejaculatevolume, depression, and anxiety. Rare ADRs includebreast tenderness and enlargement (gynecomastia), andallergic reaction.[1][2]

The FDA has notied healthcare professionals that theWarnings and Precautions section of the labels for the 5-ARI class of drugs has been revised to include new safetyinformation about the increased risk of being diagnosedwith a more serious form of prostate cancer (high-gradeprostate cancer).[3]

Finasteride is associated with intraoperative oppy irissyndrome and cataract formation.[4][5]

3 PharmacologyThe pharmacology of 5-reductase inhibition iscomplex, but involves the binding of NADPHto the enzyme followed by the substrate. Spe-cic substrates include testosterone, progesterone,androstenedione, epitestosterone, cortisol, aldosterone,and deoxycorticosterone. The entire physiologic ef-fect of their reduction is unknown, but likely relatedto their excretion or is itself physiologic.[6] Beyond

1

2 3 PHARMACOLOGY

being a catalyst in the rate-limiting step in testosteronereduction, 5-reductase isoforms I and II reduce pro-gesterone to 5-dihydroprogesterone (5-DHP) anddeoxycorticosterone to dihydrodeoxycorticosterone(DHDOC). In vitro and animal models suggest subse-quent 3-reduction of DHT, 5-DHP and DHDOClead to neurosteroid metabolites with eect on cere-bral function. These neurosteroids, which includeallopregnanolone, tetrahydrodeoxycorticosterone(THDOC), and 5-androstanediol, act as potent positiveallosteric modulators of GABAA receptors, and haveanticonvulsant, antidepressant, anxiolytic, prosexual, andanticonvulsant eects.[7] 5-dihydrocortisol is presentin the aqueous humor of the eye, is synthesized in thelens, and might help make the aqueous humor itself.[8]5-dihydroaldosterone is a potent antinatriuretic agent,although dierent from aldosterone. Its formation inthe kidney is enhanced by restriction of dietary salt,suggesting it may help retain sodium as follows:[9]

Substrate + NADPH+H+5-substrate + NADP+

5-DHP is a major hormone in circulation of normal cy-cling and pregnant women.[10]

Inhibition of the enzyme can be classied into two cate-gories: steroidal and nonsteroidal. The steroidal class hasmore inhibitors with examples including nasteride (MK-906), dutasteride (GG745), 4-MA, turosteride, MK-386,MK-434, and MK-963. Several have pursued synthesisof nonsteroidals to inhibit 5-reductase due to the unde-sired side eects of steroidals. The most potent and se-lective inhibitors of 5-R1 are found in this class, and in-clude benzoquinolones, nonsteroidal aryl acids, butanoidacid derivatives, and more recognizably, polyunsaturatedfatty acids (especially gamma-linolenic acid), zinc, andgreen tea.[6]

Inhibition of 5-reductase results in decreased conver-sion of testosterone to DHT by reducing the 4,5 double-bond. This, in turn, results in slight elevations in testos-terone and estradiol levels. Gynecomastia, sexual dys-function, and depression, are some possible side eectsof 5-reductase inhibition.Other enzymes compensate to a degree for the ab-sent conversion, specically with local expression atthe skin of reductive 17-hydroxysteroid dehydrogenase,and oxidative 3-hydroxysteroid dehydrogenase and 3-hydroxysteroid dehydrogenase enzymes.[11]

In BPH, DHT acts as a potent cellular androgen and pro-motes prostate growth; therefore, it inhibits and alleviatessymptoms of BPH. In alopecia, male and female-patternbaldness is an eect of androgenic receptor activation, soreducing levels of DHT also reduces hair loss.

3.1 PharmaceuticalsFinasteride (Proscar or Propecia) inhibits the functionof two of the isoenzymes (type II and III), whereasdutasteride inhibits all three.[12] Finasteride potently in-hibits 5-R2 at a mean inhibitory concentration IC50 of69 nM, but is less eective with 5-R1 until an IC50 of360 nM.[13] Finasteride decreases mean serum level ofDHT by 71% after 6 months,[14] and was shown in vitroto inhibit 5-R3 at a similar potency to 5-R2 in trans-fected cell lines.[15] Long term side eects can occur afterdiscontinuation of the drug.[16]

Dutasteride (Avodart) has more complete suppression ofall three 5-reductase isoenzymes. It inhibits types 1and 2 better than nasteride, leading to it causing fur-ther reduction in DHT at 6 months than the older drug(94.7% versus 70.8%).[17] It also reduces intraprostaticDHT 97% inmenwith prostate cancer at 5milligrams perday over three months.[18] A second study with 3.5 mg/dfor 4 months decreased intraprostatic DHT even furtherby 99%.[19] It has also been shown to inhibit the 5-R3isoenzyme in vitro,[20] suggesting that dutasteride may bea triple 5 reductase inhibitor in vivo.[6]

Alfatradiol (Ell-Cranell Alpha, Pantostin) is a topical 5-ARI used for androgenic alopecia in men and women.[21][22]

3.2 ResearchSome of the 5-ARIs in research are as follows:

Bexlosteride (LY-191,704) Izonsteride (LY-320,236) LY-266111 Epristeride (SKF-105,657, ONO-9302) (ONO-3805) Lapisteride (CS-891) Turosteride (FCE-26,073) FCE 28260 AS 97004 EM-402 Z-350[26]

L-751788 16-((4-chlorophenyl)oxy)4,7-dimethyl-4-azaandronstan-3-one

4-MA (Dual inhibitor of both I & II isozymes (IC50= 8.5 nM), but also 3--HSD inhibitor, investigatedextensively but said to be hepatotoxic).[27]

PNU-175706

3 MK-386 (L-733692), MK-434 (17 beta-benzoyl-4-aza-5 alpha-androst-1-ene-3-one).[28]

MK-963 (L-654066),[29]

FR146687 and FK143 (Fujisawa Pharmaceutical){Indolizine- and Indol-Butanoic Acids}

17-carboxy-4-androsten-3-one {[30] in [31]} Steroidal Oxime.[32]

Please read attached online resource for even moreinformation on the subject.[33]

For example, making the caproate ester ofDHEA (#121) seems to work well as an in-hibitor of 5-R (IC50 = 0.049nM).[34]

3.3 Basic structure of Azasteroids

N

R1

O

R

N

R

ON

R1

O

R

(A) 4-Azasteroid (B) 6-Azasteroid (C) 10-Azasteroid

R2

Basic structure of Azasteroids.

Note: the possibility for cyclopropane ring juncturebetween carbon 1 and 2 on ring A also exist in struc-ture B.

Can also functionalize carbon 4 in this struc-ture either with methyl or halogen, etc.

Some of the 6-azasteroids may prove to be useful drugs,but have yet to reach the pharmaceutical market.[35][36]

4 Herbs and other inhibitorsMany plants, as well as their associated phytochemicalconstituents, have inhibitory eects on 5-reductase.[37]In addition, many of these compounds are alsophytoestrogens.[38]

Zinc.[39]

Riboavin (vitamin B2).[40]

Azelaic acid,[39] (sometimes combined withminoxidil hair solution).

-sitosterol,[41] is just one of the many phytosterols. Polyphenols[42]

Alizarin, Curcumin, the principal curcuminoid of turmeric. Green tea catechins, including (-)-epicatechin-3-gallate, and (-)-epigallo-catechin-3-gallate(EGCG).[43]

Valoneic acid dilactone and gallagyldilactone aretwo hydrolysable tannin polyphenols isolated fromthe heartwood of Shorea laeviforia[44] and oaksspecies such as the North American white oak(Quercus alba) and European red oak (Quercusrobur) are inhibitory.[45]

Angelica koreana [46][47]

Garden Balsam or Rose Balsam (Impatiens balsam-ina)[48]

Pollen of Turnip, turnip rape, fast plants, eld mus-tard, or turnip mustard (Brassica rapa)[49]

Dodder (Cuscuta reexa)[50]

Euphorbia jolkinii[51][52]

Lingzhi mushroom or Reishi mushroom(Ganoderma lucidum)[53][54][55][56]

Ganoderic acid,[57] orGanoderol B are thoughtto be the compounds in the mushroom that arespecically active.[58]

Chinese Knotweed (Polygonum multiorum),[59]contains resveratrol-like Stilbenoids.

Black Pepper leaf extract (Piper nigrum) [60]

Red Stinkwood (Pygeum africanum)[61]

Saw Palmetto (Serenoa repens, active substance pos-sibly lauric acid[62])[63][64]

The berries of saw palmetto (Serenoa repens),a small palm native to the south east UnitedStates, possess a dual 5a-reductase inhibitionactivity, due to their high content of phy-tosterols: -sitosterol, stigmasterol, lupeol,lupenone, and cycloartenol. Permixon waslaunched in Europe in 1984 but has no FDAapproval. The lipido-sterol extract markedlyinhibits both the human isoenzymes. Type1 isoenzyme is noncompetitively (Ki = 7.2g/mL) and type 2 isoenzyme uncompetitively(Ki = 4.9 g/mL) inhibited[65]

Pine (Pinus sp. resin, active substance abieticacid)[66]

Ku Shen or Bitter root (Sophora avescens)[67]

Japanese hedge parsley (Torilis japonica)[68]

4 5 REFERENCES

Eastern Arborvitae, Northern Whitecedar (Thujaoccidentalis)[69]

Spore of Japanese climbing fern (Lygodium japon-icum)[70]

Further dual phytotherapeutic 5a-reductase in-hibitors include, among other extracts of Pygeumafricanum, Artocarpus altilis (breadfruit), Thujaorientalis, Laminaria saccharina, Arnica mon-tana, Cinchona succirubra, Eugenia caryophyllata(cloves), Humulus lupulus (hops), Hypericum per-foratum (St Johns wort), Mentha piperita (pep-permint), Rosmarinus ocinalis, Salvia ocinalis(sage) and Thymus ocinalis; furthermore, diter-pens, avins, and isoavonoids such as genistein anddaidzein, lignans, resveratrol, curcumin, and certainpolyunsaturated fatty acids.

The relative inhibitory potencies of unsaturated fattyacids are, in decreasing order: GLA, alpha-linolenicacid, linoleic acid, palmitoleic acid, oleic acid, andmyristoleic acid.[71]

Medium chain fatty acids such as those foundin coconut and the kernel of many palmfruits have also been found to inhibit 5-reductase.[72]

Certain pesticides are able to disturb the sex steroidhormone system and to act as antiandrogens.[73]

These supplements have limited testing in human clinicaltrials, and their potential for the treatment of BPH, an-drogenic alopecia, and related conditions is unknown.

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