World Journal of Pharmaceutical Research Sonam et al . World Journal of Pharmaceutical SJIF ImpactResearch Factor 5.990

Volume 4, Issue 8, 2393-2402. Review Article ISSN 2277– 7105

5-α-REDUCTASE INHIBITORS - A REVIEW

Sonam Kaushal* and Manish Sinha

Department of Pharmaceutical Chemistry, ASBASJSM College, Bela, Ropar, India.

ABSTRACT Article Received on 19 June 2015, 5-alpha reductase is an important enzyme in metabolic pathway of

Revised on 10 July 2015, . Its three subtypes SRD5A1, SRD5A2 andSRD5A3 are Accepted on 02 Aug 2015 responsible for conversion of testosterone to its more potent derivative

(DHT). Excess production of DHT leads to *Correspondence prostate cancer and alopecia. The production of DTH can be reduced For Author by inhibiting the 5-alpha reductase enzyme. Several 5-alpha reductase Sonam Kaushal Department of inhibitors were synthesized in the past and are marketed and used for Pharmaceutical the treatment of prostate cancer and baldness. The dosing of these Chemistry, ASBASJSM drugs is between 1 to 5 mg/day. The low dosing of these drugs need College, Bela, Ropar, special attention on quality control and quantitative estimation of drug India. in formulation and biological fluids. The details of 5-alpha reductase

inhibitors and the recent developments in their quantitative estimation have been compiled in the presented review.

KEYWORDS: 5-α-reductae inhibitors, cancer, quantitative estimation.

1. INTRODUCTION 1. 5-α-Reductase[1, 2, 3] 1.1. 5-α-reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in 3 metabolic pathways: bile acid biosynthesis, and metabolism. There are three isoenzymes of 5-alpha reductase, which vary in different tissues with age.

1.2. The three isoenzymes of 5-alpha reductase are: steroid 5-α-reductase 1, 2, and 3 (SRD5A1, SRD5A2 and SRD5A3). 5-α-reductase is known for converting testosterone, the male sex hormone, into the more potent dihydrotestosterone.

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1.3. 5-α-reductase 1 is present in most tissues in the body where 5-α-reductase is expressed, and is the dominant form in sebaceous glands.5-α-reductase 2 is the dominant isoenzyme in genital tissues, including the prostate. While the 5-αs-reductase 3 is expressed in liver.

1.4. 5-α-reductase has greater affinity for androgen receptors. The activity of 5-α-reductase inhibitors results in increased levels of testosterone and decreased levels of dihydrotestosterone.

1.5. 5-α-reductase inhibitors[4]: The 5-α-reductase inhibitors have androgenic effects and used primarily in the treatment of benign prostatic hyperplasia (BPH) and alopecia. These agents inhibit the enzyme 5-α-reductase that prevents conversion of testosterone, to the more potent DHT.

1.6 The drugs in this class shown in fig.1 includes (1); Bexlosteride (2); (3); Episteride (4); (5); Izonsteride (6); Turosteride (7); Lapisteride (8).

F F F

H3C Cl O OH H3C NH H H3C N H3C H H H O H H H H F F F HO O N 1 2 H H ALFATRADIOLE BEXLOSTERIDE 3 DUTASTERIDE

O NHBu O N NH S SH

O O N O N OH H H 4 5 6 EPISTERIDE FINASTERIDE IZONSTERIDE

O O NH N O O H NH H H H O N H H H O N 7 H H 8 TUROSTERIDE LAPISTERIDE Fig.1- Structure of 5-α-reductase inhibitors www.wjpr.net Vol 4, Issue 08, 2015. 2394

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2. Alfatradiol[5, 6, 7] Alfatradiol or 17α- is a 5α-reductase inhibitor used topically for the treatment of androgenic alopecia (hair loss) in men and women.

2.1 IUPAC name Estra-1,3,5(10)-triene-3,17α-diol.

2.2 Marketed preparations It is marketed under the name of pantostin, Avicis, Avixis and Ell-Cranell.

2.3. Mechanism of action Alfatradiol acts as an inhibitor of the enzyme 5-α-reductase, which is responsible for the activation of testosterone to dihydrotestosterone, and which plays a role in regulating hair growth.

2.4. Side effects Alfatradiol cause Dizziness, Headache, Nausea, Oedema (fluid retention), and Increase in weight, Skin pigmentation.

2.5. Contraindications It is not used in pregnancy or lactation condition and not to be used by patient who are less than 18 years of age.

2.6. Dose Recommended dose of alfatradiol is 0.025% in 100 ml is given once daily.

3. Bexlosteride[8, 9, 10] Bexlosteride (LY-191,704) is a potent and noncompetitive inhibitor of the enzyme 5α- reductase related to finasteride and dutasteride. It is selective for the type I isoform of the enzyme. It was never marketed.

3.1. IUPAC name (4aS,10bR)-8-chloro-4-methyl-1,2,4a,5,6,10b-hexahydrobenzo[f]quinolin.

3.2. Marketed preparations It was never marketed.

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3.3. Mechanism of action Bexlosteride is antiandrogenic as they prevent the conversion of testosterone to dihydrotestosterone (DHT). DHT is 3-5 times more potent than testosterone or other (except in skeletal muscle tissue, where testosterone is the main androgen). They are unique because they do not counteract the effects or production of other androgens other than DHT. Dihydrotestosterone is necessary for development of both external male sex organs and the prostate.

3.4. Side effects Bexlosteride cause side effects such as decreased libido, decreased ejaculate volume, depression, and anxiety. Rare ADRs include breast tenderness and enlargement (gynecomastia), and allergic reaction.

4. Dutasteride[11, 12, 13] Dutasteride is 5-α-reductase inhibitor that inhibits conversion of testosterone to dihydrotestosterone (DHT). It is used to treat benign prostatic hyperplasia.

4.1. IUPAC name (5α,17β)-N-{2, 5-Bis(triflouromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide.

4.2. Marketed preparation Marketed preparations are Avodart (soft gelatin capsule manufactured by galaxosmith).

4.3. Mechanism of action Dutasteride inhibits the conversion of testosterone to dihydrotestosterone (DHT). DHT is primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme known as 5-α-reductase, which exists as 3 isoforms, type 1 and type 2 and type 3.

Dutasteride is an inhibitor of type 1 and type 2 of 5-α-reductase isoenzymes, with which it forms a stable enzyme complex. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride does not bind to the human .

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4.4. Side effects Less serious side effects may include:  Decreased libido (sex drive);  Decreased amount of semen released during sex;  Impotence (trouble getting or keeping an erection); or  Breast enlargement.

4.5. Contraindication Dutasteride (Avodart) is contraindicated for use in  Pregnancy:- In animal reproduction and developmental toxicity studies, dutasteride inhibited development of male fetus external genitalia. Therefore, Avodart may cause fetal harm when administered to a pregnant woman. If dutasteride is used during pregnancy or if the patient becomes pregnant while taking Avodart, the patient should be apprised of the potential hazard to the fetus.  Women of childbearing potential  Pediatric patients  Patients with previously demonstrated, clinically significant hypersensitivity (e.g., serious skin reactions, angioedema) to Avodart or other 5 alpha-reductase inhibitors.

4.6. Dose The recommended dose of AVODART (Dutasteride) is 1 capsule (0.5 mg) taken once daily.

5. Episteride[14, 15, 16] Episteride is a non-competitive inhibitor of the type II isoform of the enzyme 5α-reductase, similarly to finasteride and turosteride. It was under development for the treatment of benign prostatic hyperplasia and acne vulgaris .But it was never marketed.

5.1. IUPAC name 17-(tert-butylcarbamoyl)androsta-3,5-diene-3-carboxylic acid.

5.2. Marketed preparation It was never marketed.

5.3. Mechanism of action The mechanism of episteride in the treatment of benign prostatic hyperplasia might be apoptosis stimulated by decreasing dihydrotestosterone level. www.wjpr.net Vol 4, Issue 08, 2015. 2397

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5.4. Side effects It may cause depression and many acne problems.

6. Finasteride[17, 18, 19] Finasteride is a drug used for the treatment of benign prostatic hyperplasia (BPH) and male pattern baldness (MPB).

6.1. IUPAC name N-(1,1-dimethylethyl)-3-oxo-(5α,17β)-4-azaandrost-1-ene-17-carboxamide.

6.2. Marketed preparation Finasteride cause proscar, propecia.

6.3. Mechanism of action Finasteride is a 5-α-reductase inhibitor, specifically the type II and III isoenzymes. By inhibiting 5α-reductase, finasteride prevents conversion of testosterone to dihydrotestosterone (DHT) by the type II and III isoenzymes, resulting in a decrease in serum DHT levels. By blocking DHT production, finasteride reduces androgen activity in the scalp. In the prostate, inhibition of 5-α-reductase reduces prostate volume, which improves BPH and reduces risk of prostate cancer.

6.4. Side effects It can cause hair loss (androgenic alopecia) sand allergic reaction.

6.5. Contraindication Finasteride is not approved for use in women, especially due to risks of birth defects in a fetus.

6.6. Dose The recommended dose of propecia is 1 tablet (1 mg) taken once daily. And dose for proscar is 1 tablet (5mg) taken once daily.

7. Izonsteride[20] Izonsteride is useful in the treatment of androgenic alopecia.

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7.1. IUPAC name (4aR,10bR)-8-[(4-ethyl-1,3-benzothiazol-2-yl)sulfanyl]-4,10b-dimethyl-1,4,4a,5,6,10b- hexahydrobenzo[f]quinolin-3(2H)-one.

7.2. Marketed preparation It is never marketed.

7.3. Mechanism of action It is a selective inhibitor of the 5-α-reductase, with dual effects on both the type I and type II isoforms of the enzyme. It was used for the treatment of benign prostatic hyperplasia but was never marketed. Izonsteride may also be useful in the treatment of androgenic alopecia.

7.4. Side effects It can cause anxiety, depression.

7.5. Contraindication It is not approved for use in women, especially due to risks of birth defects in a fetus.

8. Lapisteride[21, 22] Lapisteride is a dual inhibitor of both isoforms of the enzyme 5-α-reductase. It was under investigation for the treatment of benign prostatic hyperplasia (BPH) and androgenic alopecia, but was never marketed.

8.1. IUPAC name N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide.

8.2. Marketed preparation It was never marketed.

8.3. Mechanism of action It is a dual inhibitor of both isoforms of the enzyme 5-α-reductase. It was under investigation for the treatment of benign prostatic hyperplasia (BPH) and androgenic alopecia. But was never marketed.

8.4. Side effects This drug causes depression, and anxiety. Rare ADRs include breast tenderness and enlargement (gynecomastia), and allergic reaction. www.wjpr.net Vol 4, Issue 08, 2015. 2399

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9. Turosteride[23, 24, 25] Turosteride (FCE-26,073) is a selective inhibitor of the enzyme 5-α-reductase. It is useful for the treatment of acne, hair loss and mainly for androgenic alopecia.

9.1. IUPAC name (4aR,4bS,6aS,7S,9aS,9bS,11aR)-1,4a,6a-trimethyl-2-oxo-N-(propan-2-yl)-N-(propan-2- ylcarbamoyl)hexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide.

9.2. Marketed preparation It was never marketed.

9.3. Mechanism of action It is a selective inhibitor of the enzyme 5-α-reductase which was under investigation for the treatment of benign prostatic hyperplasia (BPH), but was never marketed. Similarly to finasteride, turosteride is selective for the type II isoform of 5α-redcutase, with about 15-fold selectivity for it over type I isoform of the enzyme. In animal studies it has been shown to inhibit prostate size and retard tumor growth.

9.4. Side effects Turosteride cause the side effects such as gynecomastia, erectile dysfunction and depression.

REFERENCES 1. Berger Artur, Wachter Helmut. Hunnius Pharmazeutisches Wörterbuch (in German).1998; (8): 486. 2. Frye SV, Haffner CD, Maloney PR, Mook RA, Dorsey GF, Hiner RN, Batchelor KW, Bramson HN, Stuart J.(6-Azasteroids: Potent dual inhibitors of human type 1 and 2 steroid 5-α-reductase). Journal of Medicinal Chemistry, 1993; 36(26): 4313–5. 3. Frye SV, Haffner CD, Maloney PR, Mook RA, Dorsey GF, Hiner RN, Batchelor KW, Bramson HN, Stuart J.(6-Azasteroids: Structure-Activity Relationships for Inhibition of Type 1 and 2 Human 5-α-Reductase and Human Adrenal 3β-Hydroxy-.DELTA.5-steroid Dehydrogenase/3-Keto-.DELTA.5-steroid Isomerase). Journal of Medicinal Chemistry, 1994; 37(15): 2352–60. 4. Bartsch G, Rittmaster RS, Klocker H. (Mechanism of 5-α-reductase inhibitors).World Journal of Urology, 2002; 19(6): 413-25.

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5. Finn DA, Beadles-Bohling AS, Backley EH, Ford MM, Gilliland KR, Gorin-meyer RE, Wiran KM.(A new look at 5-α-reductase inhibitor that is alfatradiole). Drug review, 2006; 12(1): 53-76. 6. Blume-Peytavi U, Kunte C, Krisp A, Garcia Bartels N, Ellwanger U, Hoffmann R.(Comparison of the efficacy and safety of topical and topical alfatradiol in the treatment of androgenetic alopecia in women). Journal of the German Society of Dermatology, 2007; 5(5): 391–395. 7. Mutschler Ernst Gerd, Geisslinge, Heyo K, Kroemer, Monika. Mechanism of alfatradiol. Wssenschaftliche Verlagsgesellschaft, (in German), 2011; (8): 453. 8. Audia JR, McQuaid LA, Neubauer BL, Rocco VP, U.S. Patent, US 5662962, 1997. 9. Flores E, Bratoeff E,Cabeza M, Ramirez E, Quiroz A, Heuze I. Steroid 5alpha-reductase inhibitors. Mini-Reviews in Medicinal Chemistry, 2003; 3(3): 225–37. 10. Rahimi-Ardabili B, Pourandarjani R, Habibollahi P, Mualeki A, Pourandarjani, Habibollahi, Mualeki. Finasteride induced depression: a prospective study. BMC Clinical Pharmacology, 2006; (6): 7. 11. Yamana K, Labrie F. Human type 3 5-α-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited by finasteride and dutasteride. Hormone Molecular Biology and Clinical Investigation, 2010; 2(3): 293–299. 12. Keam SJ, Scott LJ. Dutasteride: a review of its use in the management of prostate disorders 2008; 68(4): 463-85. 13. Shah SK, Trump DL, Sartor O, Tan W, Wilding GE, Mohler JL.Phase II study of Dutasteride for recurrent prostate cancer during androgen deprivation therapy. 2009; 181(2): 621-626. 14. Hedge SS. Episteride SmithKline Beecham I Drugs. (The Drugs Journal 1). 1998; (1): 152–7. 15. Berthaut I, Mestayer C, Portois MC, Cussenot O, Mowszowicz I. Pharmacological and molecular evidence for the expression of the two steroid 5 alpha-reductase isozymes in normal and hyperplastic human prostatic cells in culture. 1997; 32 (3): 155–63. 16. Sun ZY, Wu HY, Wang MY, Tu ZH.(5-α-reductase inhibitor that is Episteride).European Journal of Pharmacology, 1999; 29; 371(2-3): 227-33. 17. Drury JE, Di Costanzo L, Penning TM, Christianson DW. (Inhibition of human steroid 5beta-reductase (AKR1D1) by finasteride and structure of the enzyme-inhibitor complex). The Journal of Biological Chemistry, 2009; 284(30): 19786–90.

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18. Morton IK. Concise Dictionary of Pharmacological Agents: Properties and Synonyms. 2012, (Springer Science & Business Media):121-246. 19. Aggarwal, S; Thareja, S; Verma, A; Bhardwaj, T.R; Kumar, M "An overview on 5alpha- reductase inhibitors, 2010; 75 (2): 109–53. 20. Chang Chawnshang. Androgens and androgen receptor: mechanisms, functions, and clinical application. 2002, (Boston: Kluwer Academic Publishers), 7184-7187. 21. Niiyama SS, Kojima K, Hamada T, Happle R, Hoffmann. (The novel drug CS-891 inhibits 5alpha-reductase activity in freshly isolated dermal papilla of human hair follicles). European Journal of Dermatology, 2000; 10(8): 593–5. 22. Yada S, Ohya M, Ohuchi Y.(Solid phase transition of CS-891 enantiotropes during grinding). International Journal of Pharmaceutics, 2003; 255(1-2): 69–79. 23. Zaccheo T, Giudici D, di Salle E. Effect of turosteride, a 5 alpha-reductase inhibitor, on the Dunning R3327 rat prostatic carcinoma, 1997; 30(2): 85–91. 24. Iehle C, Delos S, Guirou O, Tate R, Raynaud JP, Martin PM. (Human prostatic steroid 5 alpha-reductase isoforms--a comparative study of selective inhibitors). The Journal of Steroid Biochemistry and Molecular Biology, 1995; 54(5-6): 273–9. 25. di Salle E, Giudici D, Briatico G, Ornati G, Panzeri.(Hormonal effects of turosteride, a 5- α-reductase inhibitor, in the rat). The Journal of Steroid Biochemistry and Molecular Biology, 1993; 46(5): 549–55.

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