A Review of the Azasteroid-type 5-alpha Reductase Inhibitors for the Management of Benign Prostatic Hyperplasia

Girish   Chandra   Arya; Ankit      Rathee; Shefali      Mehla; Preeti      Bisht; Rajiv      Sharma
doi:10.2174/0115701808241219230923154750
Abstract

Background: Prostate cancer is one of the most complex cancer and most common in elderly males. The prostate gland's malignant growth known as benign prostatic hyperplasia (BPH) is associated with lower urinary tract symptoms (LUTS) such as frequency hesitancy, and urgency. Various treatment strategies have been employed for management of prostate cancer. Due to its prolonged treatment, varying clinical treatment and high association with treatment related morbidity raise serious questions about the ideal treatment strategy for the patients. Except for skin cancer, prostate cancer is the most frequent cancer among men.
Introduction: Prostate cancer cases were estimated at 14, 14,259 and 3, 75,304 persons were died globally in 2020. It is the fourth most frequent type of cancer to be discovered worldwide. It impacts over 75% of people by the time they turn 65 and its prevalence increases with age. It seems sensible that 5-alpha reductase inhibitors prevent the conversion of testosterone to dihydrotestosterone and would be used to treat benign prostatic hyperplasia because high levels of the 5-alpha reductase enzymes in humans lead to excessive levels of dihydrotestosterone in peripheral tissues.
Methods: Finasteride (Proscar) and dutasteride (Avodart) are 5-alpha reductase inhibitors (5-ARIs) used in the treatment of lower urinary tract symptoms (LUTS) with prostatic enlargement as these suppress the androgens. Finasteride in clinical trials shows 25% reduction in prostate cancer in randomized trials. Dutasteride (Avodart) shows the reduction in risk of prostate cancer by 23% (approx.) but it also affect the detection of prostate cancer by affecting the levels of prostate-specific antigen.
Results: The structural requirements for potential 5-alpha reductase inhibitors might be revealed via ligand-based comparative pharmacophore research employing the known strong inhibitors. These approaches can generate data can be utilized to create more effective and selective inhibitors that pharmaceutical industries can produce at a lesser price.
Conclusion: 5-alpha reductase inhibitors are useful in the management of prostate cancer. However, further studies are needed to elucidate the optimal utilization, long-term effects and potential risks in prostate cancer treatment. All 5-alpha reductase inhibitor subcategories have been addressed in this review.
« Previous Next »
[1]
Tiwari, A.; Krishna, N.S.; Nanda, K.; Chugh, A. Benign prostatic hyperplasia: An insight into current investigational medical therapies. Expert Opin. Investig. Drugs,  2005, 14(11), 1359-1372.
 [http://dx.doi.org/10.1517/13543784.14.11.1359] [PMID:  16255676]

[2]
Vickman, R.E.; Franco, O.E.; Moline, D.C.; Vander Griend, D.J.; Thumbikat, P.; Hayward, S.W. The role of the androgen receptor in prostate development and benign prostatic hyperplasia: A review. Asian J. Urol.,  2020, 7(3), 191-202.
 [http://dx.doi.org/10.1016/j.ajur.2019.10.003] [PMID:  32742923]

[3]
Hieble, J.P. Therapeutic strategies for benign prostatic hypertrophy. Drug Discov. Today Ther. Strateg.,  2004, 1(2), 243-248.
 [http://dx.doi.org/10.1016/j.ddstr.2004.08.022]

[4]
Kenny, B.; Ballard, S.; Blagg, J.; Fox, D. Pharmacological options in the treatment of benign prostatic hyperplasia. J. Med. Chem.,  1997, 40(9), 1293-1315.
 [http://dx.doi.org/10.1021/jm960697s] [PMID:  9135028]

[5]
Andersson, K.E.; de Groat, W.C.; McVary, K.T.; Lue, T.F.; Maggi, M.; Roehrborn, C.G.; Wyndaele, J.J.; Melby, T.; Viktrup, L. Tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: Pathophysiology and mechanism(s) of action. Neurourol. Urodyn.,  2011, 30(3), 292-301.
 [http://dx.doi.org/10.1002/nau.20999] [PMID:  21284024]

[6]
Burnett, A.L.; Wein, A.J. Benign prostatic hyperplasia in primary care: What you need to know. J. Urol.,  2006, 175(3 Pt 2), S19-S24.
 [http://dx.doi.org/10.1016/S0022-5347(05)00310-1] [PMID:  16458735]

[7]
Kulig, K.; Malawska, B. Trends in the development of new drugs for treatment of benign prostatic hyperplasia. Curr. Med. Chem.,  2006, 13(28), 3395-3416.
 [http://dx.doi.org/10.2174/092986706779010315] [PMID:  17168713]

[8]
Rassweiler, J.; Teber, D.; Kuntz, R.; Hofmann, R. Complications of transurethral resection of the prostate (TURP)--incidence, management, and prevention. Eur. Urol.,  2006, 50(5), 969-979.
 [http://dx.doi.org/10.1016/j.eururo.2005.12.042] [PMID:  16469429]

[9]
Dull, P.; Reagan, R.W., Jr; Bahnson, R.R. Managing benign prostatic hyperplasia. Am. Fam. Physician,  2002, 66(1), 77-84.
 [PMID:  12126034]

[10]
Fitzpatrick, J.M.; Artibani, W. Therapeutic strategies for managing BPH progression. Eur. Urol. Suppl.,  2006, 5(20), 997-1003.
 [http://dx.doi.org/10.1016/j.eursup.2006.08.009]

[11]
Li, X.; Chen, C.; Singh, S.M.; Labire, F. The enzyme and inhibitors of 4-ene-3-oxosteroid 5α-oxidoreductase. Steroids,  1995, 60(6), 430-441.
 [http://dx.doi.org/10.1016/0039-128X(95)00021-H] [PMID:  7676475]

[12]
Flores, E.; Bratoeff, E.; Cabeza, M.; Ramirez, E.; Quiroz, A.; Heuze, I. Steroid 5α-reductase inhibitors. Mini Rev. Med. Chem.,  2003, 3(3), 225-237.
 [http://dx.doi.org/10.2174/1389557033488196] [PMID:  12570838]

[13]
Tarter, T.H.; Vaughan, E.D. Jr Inhibitors of 5α-reductase in the treatment of benign prostatic hyperplasia. Curr. Pharm. Des.,  2006, 12(7), 775-783.
 [http://dx.doi.org/10.2174/138161206776056010] [PMID:  16515494]

[14]
Mobley, D.; Feibus, A.; Baum, N. Benign prostatic hyperplasia and urinary symptoms: Evaluation and treatment. Postgrad. Med.,  2015, 127(3), 301-307.
 [http://dx.doi.org/10.1080/00325481.2015.1018799] [PMID:  25823641]

[15]
Abrams, P.; Chapple, C.; Khoury, S.; Roehrborn, C.; de la Rosette, J. Evaluation and treatment of lower urinary tract symptoms in older men. J. Urol.,  2009, 181(4), 1779-1787.
 [http://dx.doi.org/10.1016/j.juro.2008.11.127] [PMID:  19233402]

[16]
Dunn, M.W.; Kazer, M.W. Prostate cancer overview. In: Seminars in oncology nursing; Elsevier, 2011. 
 [http://dx.doi.org/10.1016/j.soncn.2011.07.002]

[17]
Culp, M.B.; Soerjomataram, I.; Efstathiou, J.A.; Bray, F.; Jemal, A. Recent global patterns in prostate cancer incidence and mortality rates. Eur. Urol.,  2020, 77(1), 38-52.
 [http://dx.doi.org/10.1016/j.eururo.2019.08.005] [PMID:  31493960]

[18]
Ferlay, J. Global cancer observatory: Cancer today. 2019. Available from:
          https://gco.iarc.fr/today/home

[19]
Bill-Axelson, A.; Holmberg, L.; Garmo, H.; Rider, J.R.; Taari, K.; Busch, C.; Nordling, S.; Häggman, M.; Andersson, S-O.; Spångberg, A.; Andrén, O.; Palmgren, J.; Steineck, G.; Adami, H-O.; Johansson, J-E. Radical prostatectomy or watchful waiting in early prostate cancer. N. Engl. J. Med.,  2014, 370(10), 932-942.
 [http://dx.doi.org/10.1056/NEJMoa1311593] [PMID:  24597866]

[20]
Giannarini, G.; Petralia, G.; Thoeny, H.C. Potential and limitations of diffusion-weighted magnetic resonance imaging in kidney, prostate, and bladder cancer including pelvic lymph node staging: A critical analysis of the literature. Eur. Urol.,  2012, 61(2), 326-340.
 [http://dx.doi.org/10.1016/j.eururo.2011.09.019] [PMID:  22000497]

[21]
Yaxley, J.W.; Coughlin, G.D.; Chambers, S.K.; Occhipinti, S.; Samaratunga, H.; Zajdlewicz, L.; Dunglison, N.; Carter, R.; Williams, S.; Payton, D.J.; Perry-Keene, J.; Lavin, M.F.; Gardiner, R.A. Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: Early outcomes from a randomised controlled phase 3 study. Lancet,  2016, 388(10049), 1057-1066.
 [http://dx.doi.org/10.1016/S0140-6736(16)30592-X] [PMID:  27474375]

[22]
Moran, P.S.; O’Neill, M.; Teljeur, C.; Flattery, M.; Murphy, L.A.; Smyth, G.; Ryan, M. Robot-assisted radical prostatectomy compared with open and laparoscopic approaches: A systematic review and meta-analysis. Int. J. Urol.,  2013, 20(3), 312-321.
 [http://dx.doi.org/10.1111/iju.12070] [PMID:  23311943]

[23]
Moncada, I.; López, I.; Ascencios, J.; Krishnappa, P.; Subirá, D. Complications of robot assisted radical prostatectomy. Arch. Esp. Urol.,  2019, 72(3), 266-276.
 [PMID:  30945653]

[24]
Hamdy, F.C.; Donovan, J.L.; Lane, J.A.; Mason, M.; Metcalfe, C.; Holding, P.; Davis, M.; Peters, T.J.; Turner, E.L.; Martin, R.M.; Oxley, J.; Robinson, M.; Staffurth, J.; Walsh, E.; Bollina, P.; Catto, J.; Doble, A.; Doherty, A.; Gillatt, D.; Kockelbergh, R.; Kynaston, H.; Paul, A.; Powell, P.; Prescott, S.; Rosario, D.J.; Rowe, E.; Neal, D.E. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N. Engl. J. Med.,  2016, 375(15), 1415-1424.
 [http://dx.doi.org/10.1056/NEJMoa1606220] [PMID:  27626136]

[25]
Hannoun-Lévi, J.M. Brachytherapy for prostate cancer: Present and future. Cancer Radiother.,  2017, 21(6-7), 469-472.
 [http://dx.doi.org/10.1016/j.canrad.2017.06.009] [PMID:  28847460]

[26]
Nguyen-Nielsen, M.; Borre, M. Diagnostic and therapeutic strategies for prostate cancer. In: Seminars in nuclear medicine; Elsevier, 2016. 
 [http://dx.doi.org/10.1053/j.semnuclmed.2016.07.002]

[27]
Cohen, J.K. Cryosurgery of the prostate: Techniques and indications. Rev. Urol.,  2004, 6(Suppl. 4), S20-S26.
 [PMID:  16985866]

[28]
Saginala, K.; Barsouk, A.; Aluru, J.S.; Rawla, P.; Padala, S.A.; Barsouk, A. Epidemiology of bladder cancer. Med. Sci.,  2020, 8(1), 15.
 [http://dx.doi.org/10.3390/medsci8010015] [PMID:  32183076]

[29]
Barsouk, A.; Padala, S.A.; Vakiti, A.; Mohammed, A.; Saginala, K.; Thandra, K.C.; Rawla, P.; Barsouk, A. Epidemiology, staging and management of prostate cancer. Med. Sci.,  2020, 8(3), 28.
 [http://dx.doi.org/10.3390/medsci8030028] [PMID:  32698438]

[30]
Beer, T.M.; Armstrong, A.J.; Rathkopf, D.E.; Loriot, Y.; Sternberg, C.N.; Higano, C.S.; Iversen, P.; Bhattacharya, S.; Carles, J.; Chowdhury, S.; Davis, I.D.; de Bono, J.S.; Evans, C.P.; Fizazi, K.; Joshua, A.M.; Kim, C-S.; Kimura, G.; Mainwaring, P.; Mansbach, H.; Miller, K.; Noonberg, S.B.; Perabo, F.; Phung, D.; Saad, F.; Scher, H.I.; Taplin, M-E.; Venner, P.M.; Tombal, B. Enzalutamide in metastatic prostate cancer before chemotherapy. N. Engl. J. Med.,  2014, 371(5), 424-433.
 [http://dx.doi.org/10.1056/NEJMoa1405095] [PMID:  24881730]

[31]
Hussain, M.; Fizazi, K.; Saad, F.; Rathenborg, P.; Shore, N.; Ferreira, U.; Ivashchenko, P.; Demirhan, E.; Modelska, K.; Phung, D.; Krivoshik, A.; Sternberg, C.N. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N. Engl. J. Med.,  2018, 378(26), 2465-2474.
 [http://dx.doi.org/10.1056/NEJMoa1800536] [PMID:  29949494]

[32]
Fizazi, K.; Shore, N.; Tammela, T.L.; Ulys, A.; Vjaters, E.; Polyakov, S.; Jievaltas, M.; Luz, M.; Alekseev, B.; Kuss, I.; Kappeler, C.; Snapir, A.; Sarapohja, T.; Smith, M.R. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N. Engl. J. Med.,  2019, 380(13), 1235-1246.
 [http://dx.doi.org/10.1056/NEJMoa1815671] [PMID:  30763142]

[33]
Schmid, S.C.; Geith, A.; Böker, A.; Tauber, R.; Seitz, A.K.; Kuczyk, M.; von Klot, C.; Gschwend, J.E.; Merseburger, A.S.; Retz, M. Enzalutamide after docetaxel and abiraterone therapy in metastatic castration-resistant prostate cancer. Adv. Ther.,  2014, 31(2), 234-241.
 [http://dx.doi.org/10.1007/s12325-014-0092-1] [PMID:  24442834]

[34]
Antonarakis, E.S.; Piulats, J.M.; Gross-Goupil, M.; Goh, J.; Ojamaa, K.; Hoimes, C.J.; Vaishampayan, U.; Berger, R.; Sezer, A.; Alanko, T.; de Wit, R.; Li, C.; Omlin, A.; Procopio, G.; Fukasawa, S.; Tabata, K.I.; Park, S.H.; Feyerabend, S.; Drake, C.G.; Wu, H.; Qiu, P.; Kim, J.; Poehlein, C.; de Bono, J.S. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: Multicohort, open-label phase II KEYNOTE-199 study. J. Clin. Oncol.,  2020, 38(5), 395-405.
 [http://dx.doi.org/10.1200/JCO.19.01638] [PMID:  31774688]

[35]
Graff, J.N.; Alumkal, J.J.; Drake, C.G.; Thomas, G.V.; Redmond, W.L.; Farhad, M.; Cetnar, J.P.; Ey, F.S.; Bergan, R.C.; Slottke, R.; Beer, T.M. Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget,  2016, 7(33), 52810-52817.
 [http://dx.doi.org/10.18632/oncotarget.10547] [PMID:  27429197]

[36]
Nevedomskaya, E.; Baumgart, S.J.; Haendler, B. Recent advances in prostate cancer treatment and drug discovery. Int. J. Mol. Sci.,  2018, 19(5), 1359.
 [http://dx.doi.org/10.3390/ijms19051359] [PMID:  29734647]

[37]
Smith, M.R.; Hussain, M.; Saad, F.; Fizazi, K.; Sternberg, C.N.; Crawford, E.D.; Kopyltsov, E.; Park, C.H.; Alekseev, B.; Montesa-Pino, Á.; Ye, D.; Parnis, F.; Cruz, F.; Tammela, T.L.J.; Suzuki, H.; Utriainen, T.; Fu, C.; Uemura, M.; Méndez-Vidal, M.J.; Maughan, B.L.; Joensuu, H.; Thiele, S.; Li, R.; Kuss, I.; Tombal, B. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N. Engl. J. Med.,  2022, 386(12), 1132-1142.
 [http://dx.doi.org/10.1056/NEJMoa2119115] [PMID:  35179323]

[38]
Cattrini, C.; Caffo, O.; De Giorgi, U.; Mennitto, A.; Gennari, A.; Olmos, D.; Castro, E. Apalutamide, darolutamide and enzalutamide for nonmetastatic castration-resistant prostate cancer (nmCRPC): A critical review. Cancers,  2022, 14(7), 1792.
 [http://dx.doi.org/10.3390/cancers14071792] [PMID:  35406564]

[39]
Rao, A.; Antonarakis, E.S. The growing role of rucaparib in contemporary treatment of metastatic prostate cancer: A review of efficacy and guidance for side effect management. Expert Rev. Anticancer Ther.,  2022, 22(7), 671-679.
 [http://dx.doi.org/10.1080/14737140.2022.2081154] [PMID:  35594523]

[40]
Antonarakis, E.S.; Gomella, L.G.; Petrylak, D.P. When and how to use PARP inhibitors in prostate cancer: A systematic review of the literature with an update on on-going trials. Eur. Urol. Oncol.,  2020, 3(5), 594-611.
 [http://dx.doi.org/10.1016/j.euo.2020.07.005] [PMID:  32814685]

[41]
Clarke, N.W. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid.,  2022, 1(9), EVIDoa2200043.
 [http://dx.doi.org/10.1056/EVIDoa2200043]

[42]
Chan, T.G.; O’Neill, E.; Habjan, C.; Cornelissen, B. Combination strategies to improve targeted radionuclide therapy. J. Nucl. Med.,  2020, 61(11), 1544-1552.
 [http://dx.doi.org/10.2967/jnumed.120.248062] [PMID:  33037092]

[43]
Kyprianou, N.; Isaacs, J.T. Quantal relationship between prostatic dihydrotestosterone and prostatic cell content: Critical threshold concept. Prostate,  1987, 11(1), 41-50.
 [http://dx.doi.org/10.1002/pros.2990110106] [PMID:  3658827]

[44]
Singh, V.; Sheikh, A.; Abourehab, M.A.S.; Kesharwani, P. Dostarlimab as a miracle drug: Rising hope against cancer treatment. Biosensors,  2022, 12(8), 617.
 [http://dx.doi.org/10.3390/bios12080617] [PMID:  36005013]

[45]
Lee, C. Role of androgen in prostate growth and regression: Stromal-epithelial interaction. Prostate Suppl.,  1996, 6(S6), 52-56.
 [http://dx.doi.org/10.1002/(SICI)1097-0045(1996)6+<52::AID-PROS10>3.0.CO;2-Q] [PMID:  8630230]

[46]
Carson, C., III; Rittmaster, R. The role of dihydrotestosterone in benign prostatic hyperplasia. Urology,  2003, 61(4(S1)), 2-7.
 [http://dx.doi.org/10.1016/S0090-4295(03)00045-1] [PMID:  12657354]

[47]
Björkhem, I. Mechamism and stereochemistry of the enzymatic conversion of a delta 4-3-oxosteroid into a 3-oxo-5α-steroid. Eur. J. Biochem.,  1969, 8(3), 345-351.
 [http://dx.doi.org/10.1111/j.1432-1033.1969.tb00534.x] [PMID:  4389862]

[48]
Holland, H.L.; Xu, W.; Hughes, D.W. Stereochemistry of reduction by the 5α-reductase enzyme of Penicillium decumbens and the 1 H NMR assignment of 5α-dihydrotestosterone. J. Chem. Soc. Chem. Commun.,  1989, (22), 1760-1761.
 [http://dx.doi.org/10.1039/C39890001760]

[49]
Andersson, S.; Russell, D.W. Structural and biochemical properties of cloned and expressed human and rat steroid 5 alpha-reductases. Proc. Natl. Acad. Sci.,  1990, 87(10), 3640-3644.
 [http://dx.doi.org/10.1073/pnas.87.10.3640] [PMID:  2339109]

[50]
Labrie, F.; Sugimoto, Y.; Luu-The, V.; Simard, J.; Lachance, Y.; Bachvarov, D.; Leblanc, G.; Durocher, F.; Paquet, N. Structure of human type II 5 alpha-reductase gene. Endocrinology,  1992, 131(3), 1571-1573.
 [http://dx.doi.org/10.1210/endo.131.3.1505484] [PMID:  1505484]

[51]
Wilson, J.D.; Griffin, J.E.; Russell, D.W. Steroid 5 α-reductase 2 deficiency. Endocr. Rev.,  1993, 14(5), 577-593.
 [http://dx.doi.org/10.1210/edrv-14-5-577] [PMID:  8262007]

[52]
Andersson, S.; Berman, D.M.; Jenkins, E.P.; Russell, D.W. Deletion of steroid 5 α-reductase 2 gene in male pseudohermaphroditism. Nature,  1991, 354(6349), 159-161.
 [http://dx.doi.org/10.1038/354159a0] [PMID:  1944596]

[53]
Poletti, A.; Coscarella, A.; Negri-Cesi, P.; Colciago, A.; Celotti, F.; Martini, L. 5 α-reductase isozymes in the central nervous system. Steroids,  1998, 63(5-6), 246-251.
 [http://dx.doi.org/10.1016/S0039-128X(98)00018-X] [PMID:  9618779]

[54]
Singh, H. Azasteroids: Syntheses and significance. Indian J. Pharm. Edu.,  1970, 4(2), 2-20.

[55]
Singh, H.; Jindal, D.P.; Yadav, M.R.; Kumar, M. Heterosteroids and drug research. Prog. Med. Chem.,  1991, 28, 233-300.
 [http://dx.doi.org/10.1016/S0079-6468(08)70366-7] [PMID:  1843548]

[56]
Doorenbos, N.; Wu, M. Notes- Steroids. III. Synthesis of some 3-Aza-A-homocholestanes by the beckmann and schmidt rearrangements in polyphosphoric acid. J. Org. Chem.,  1961, 26(7), 2548-2549.
 [http://dx.doi.org/10.1021/jo01351a614]

[57]
Vlattas, I. Studies in steroids and alkaloids; University of British Columbia, 1966. 

[58]
Voigt, W.; Hsia, S.L. Further studies on testosterone 5 -reductase of human skin. Structural features of steroid inhibitors. J. Biol. Chem.,  1973, 248(12), 4280-4285.
 [http://dx.doi.org/10.1016/S0021-9258(19)43769-1] [PMID:  4711608]

[59]
Haffner, C. An efficient synthesis of 3-pyridyl-N-oxide steroides: Inhibitors of 5α-reductase. Tetrahedron Lett.,  1994, 35(9), 1349-1352.
 [http://dx.doi.org/10.1016/S0040-4039(00)76215-0]

[60]
Robinson, A.J.; DeLucca, I.; Drummond, S.; Boswell, G.A. Steroidal nitrone inhibitors of 5α-reductase. Tetrahedron Lett.,  2003, 44(25), 4801-4804.
 [http://dx.doi.org/10.1016/S0040-4039(03)00741-X]

[61]
Voigt, W.; Fernandez, E.P.; Hsia, S.L. Transformation of testosterone into 17 β-hydroxy-5 α-androstan-3-one by microsomal preparations of human skin. J. Biol. Chem.,  1970, 245(21), 5594-5599.
 [http://dx.doi.org/10.1016/S0021-9258(18)62696-1] [PMID:  4394353]

[62]
Rasmusson, G.H. Preparation of 4-aza-17-substituted-5α-androstan-3-ones useful as 5α-reductase inhibitors. US4220775A, 1980.

[63]
Witzel, B.E. 17-Ethers and thioethers of 4-aza-steroids. US5536727A, 1996.

[64]
Durette, P.L. 16-substituted-4-aza-3-oxo-androstane as 5-alpha-reductase isozyme 1 inhibitors. US5739137A, 1998.

[65]
Harris, G.; Tolman, R.L.; Sahoo, S.P. 17-alkyl-7-substituted-4-aza steroid derivatives as 5-α-reductase inhibitors. US5763361A, 1998.

[66]
Chan, W.K.; Fong, C.Y.; Tiong, H.H.; Tan, C.H. The inhibition of 3 β HSD activity in porcine granulosa cells by 4-MA, a potent 5 α-reductase inhibitor. Biochem. Biophys. Res. Commun.,  1987, 144(1), 166-171.
 [http://dx.doi.org/10.1016/S0006-291X(87)80490-4] [PMID:  3107552]

[67]
Brandt, M.; Levy, M.A. 3 Beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase from bovine adrenals: Mechanism of inhibition by 3-oxo-4-aza steroids and kinetic mechanism of the dehydrogenase. Biochemistry,  1989, 28(1), 140-148.
 [http://dx.doi.org/10.1021/bi00427a021] [PMID:  2706240]

[68]
McConnell, J.D. Androgen ablation and blockade in the treatment of benign prostatic hyperplasia. Urol. Clin. North Am.,  1990, 17(3), 661-670.
 [http://dx.doi.org/10.1016/S0094-0143(21)00978-2] [PMID:  1695786]

[69]
Faller, B.; Farley, D.; Nick, H. Finasteride: A slow-binding 5 alpha-reductase inhibitor. Biochemistry,  1993, 32(21), 5705-5710.
 [http://dx.doi.org/10.1021/bi00072a028] [PMID:  8389191]

[70]
Vaughan, D.; Imperato-McGinley, J.; McConnell, J.; Matsumoto, A.M.; Bracken, B.; Roy, J.; Sullivan, M.; Pappas, F.; Cook, T.; Daurio, C.; Meehan, A.; Stoner, E.; Waldstreicher, J. Long-term (7 to 8-year) experience with finasteride in men with benign prostatic hyperplasia. Urology,  2002, 60(6), 1040-1044.
 [http://dx.doi.org/10.1016/S0090-4295(02)01971-4] [PMID:  12475666]

[71]
Bull, H.G.; Garcia-Calvo, M.; Andersson, S.; Baginsky, W.F.; Chan, H.K.; Ellsworth, D.E.; Miller, R.R.; Stearns, R.A.; Bakshi, R.K.; Rasmusson, G.H.; Tolman, R.L.; Myers, R.W.; Kozarich, J.W.; Harris, G.S. Mechanism-based inhibition of human steroid 5α-reductase by finasteride: Enzyme-catalyzed formation of NADP− dihydrofinasteride, a potent bisubstrate analog inhibitor. J. Am. Chem. Soc.,  1996, 118(10), 2359-2365.
 [http://dx.doi.org/10.1021/ja953069t]

[72]
Harris, G.S.; Kozarich, J.W. Steroid 5α-reductase inhibitors in androgen-dependent disorders. Curr. Opin. Chem. Biol.,  1997, 1(2), 254-259.
 [http://dx.doi.org/10.1016/S1367-5931(97)80017-8] [PMID:  9667860]

[73]
Weintraub, P.M.; Blohm, T.R.; Laughlin, M. Preparation of 20-(hydroxymethyl)-4-methyl-4-aza-2-oxa-5 alpha-pregnan-3-one as an inhibitor of testosterone 5 alpha-reductase. J. Med. Chem.,  1985, 28(6), 831-833.
 [http://dx.doi.org/10.1021/jm00383a026] [PMID:  4009607]

[74]
Bakshi, R.K.; Rasmusson, G.H.; Patel, G.F.; Mosley, R.T.; Chang, B.; Ellsworth, K.; Harris, G.S.; Tolman, R.L. 4-Aza-3-oxo-5 alpha-androst-1-ene-17 beta-N-aryl-carboxamides as dual inhibitors of human type 1 and type 2 steroid 5 alpha-reductases. Dramatic effect of N-aryl substituents on type 1 and type 2 5 alpha-reductase inhibitory potency. J. Med. Chem.,  1995, 38(17), 3189-3192.
 [http://dx.doi.org/10.1021/jm00017a001] [PMID:  7650670]

[75]
Roehrborn, C.G.; Boyle, P.; Nickel, J.C.; Hoefner, K.; Andriole, G. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology,  2002, 60(3), 434-441.
 [http://dx.doi.org/10.1016/S0090-4295(02)01905-2] [PMID:  12350480]

[76]
Stuart, J.D.; Lee, F.W.; Simpson Noel, D.; Kadwell, S.H.; Overton, L.K.; Hoffman, C.R.; Kost, T.A.; Tippin, T.K.; Yeager, R.L.; Batchelor, K.W.; Bramson, H.N. Pharmacokinetic parameters and mechanisms of inhibition of rat type 1 and 2 steroid 5α-reductases: Determinants for different in vivo activities of GI198745 and finasteride in the rat. Biochem. Pharmacol.,  2001, 62(7), 933-942.
 [http://dx.doi.org/10.1016/S0006-2952(01)00728-6] [PMID:  11543729]

[77]
Evans, H.C.; Goa, K.L. Dutasteride. Drugs Aging,  2003, 20(12), 905-916.
 [http://dx.doi.org/10.2165/00002512-200320120-00005] [PMID:  14565784]

[78]
Schulman, C.; Pommerville, P.; Höfner, K.; Wachs, B. Long-term therapy with the dual 5α-reductase inhibitor dutasteride is well tolerated in men with symptomatic benign prostatic hyperplasia. BJU Int.,  2006, 97(1), 73-79.
 [http://dx.doi.org/10.1111/j.1464-410X.2005.05909.x] [PMID:  16336332]

[79]
Brown, C.T.; Nuttall, M.C. Dutasteride: A new 5-alpha reductase inhibitor for men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. Int. J. Clin. Pract.,  2003, 57(8), 705-709.
 [http://dx.doi.org/10.1111/j.1742-1241.2003.tb10592.x] [PMID:  14627182]

[80]
Clark, R.V.; Hermann, D.J.; Cunningham, G.R.; Wilson, T.H.; Morrill, B.B.; Hobbs, S. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5α-reductase inhibitor. J. Clin. Endocrinol. Metab.,  2004, 89(5), 2179-2184.
 [http://dx.doi.org/10.1210/jc.2003-030330] [PMID:  15126539]

[81]
Djavan, B.; Milani, S.; Fong, Y.K. Dutasteride: A novel dual inhibitor of 5α-reductase for benign prostatic hyperplasia. Expert Opin. Pharmacother.,  2005, 6(2), 311-317.
 [http://dx.doi.org/10.1517/14656566.6.2.311] [PMID:  15757426]

[82]
Andriole, G.L.; Kirby, R. Safety and tolerability of the dual 5α-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia. Eur. Urol.,  2003, 44(1), 82-88.
 [http://dx.doi.org/10.1016/S0302-2838(03)00198-2] [PMID:  12814679]

[83]
Di Salle, E.; Briatico, G.; Giudici, D.; Ornati, G.; Nesi, M.; Panzeri, A. 17 β-acylurea derivatives of 4-azasteroids as inhibitors of testosterone 5 α-reductase. J. Steroid Biochem. Mol. Biol.,  1992, 41(3-8), 765-768.
 [http://dx.doi.org/10.1016/0960-0760(92)90420-N] [PMID:  1373305]

[84]
Di Salle, E.; Briatico, G.; Giudici, D.; Ornati, G.; Panzeri, A. Endocrine properties of the testosterone 5 α-reductase inhibitor turosteride (FCE 26073). J. Steroid Biochem. Mol. Biol.,  1994, 48(2-3), 241-248.
 [http://dx.doi.org/10.1016/0960-0760(94)90151-1] [PMID:  8142301]

[85]
Rasmusson, G.H.; Reynolds, G.F.; Utne, T.; Jobson, R.B.; Primka, R.L.; Berman, C.; Brooks, J.R. Azasteroids as inhibitors of rat prostatic 5 alpha-reductase. J. Med. Chem.,  1984, 27(12), 1690-1701.
 [http://dx.doi.org/10.1021/jm00378a028] [PMID:  6502599]

[86]
Lourdusamy, M.; Côté, J.; Laplante, S.; Labrie, F.; Singh, S.M. Synthesis and in vitro study of 17 β-[N-ureylene-N,N′-disubstituted]-4-methyl-4-aza-5 α-androstan-3-ones as selective inhibitors of type I 5 α-reductase. Bioorg. Med. Chem.,  1997, 5(2), 305-310.
 [http://dx.doi.org/10.1016/S0968-0896(96)00241-6] [PMID:  9061195]

[87]
Bakshi, R.K.; Patel, G.F.; Rasmusson, G.H.; Baginsky, W.F.; Cimis, G.; Ellsworth, K.; Chang, B.; Bull, H.; Tolman, R.L.; Harris, G.S. 4,7 beta-Dimethyl-4-azacholestan-3-one (MK-386) and related 4-azasteroids as selective inhibitors of human type 1 5 alpha-reductase. J. Med. Chem.,  1994, 37(23), 3871-3874.
 [http://dx.doi.org/10.1021/jm00049a003] [PMID:  7966146]

[88]
Ellsworth, K.; Azzolina, B.; Baginsky, W.; Bull, H.; Chang, B.; Cimis, G.; Mitra, S.; Toney, J.; Bakshi, R.K.; Rasmusson, G.R.; Tolman, R.L.; Harris, G.S. MK386: A potent, selective inhibitor of the human type 1 5α-reductase. J. Steroid Biochem. Mol. Biol.,  1996, 58(4), 377-384.
 [http://dx.doi.org/10.1016/0960-0760(96)00050-7] [PMID:  8903421]

[89]
Xun Li, ; Singh, S.M.; Lourdusamy, M.; Mérand, Y.; Veilleux, R.; Labrie, F. Synthesis and in vitro antiandrogenic activity of 17β-hydroxy-17α-(ω-hydroxy/haloalkyn-1′-yl)-4-methyl-4-aza-3-oxo-5α-androstan-(1-ene)-3-ones. Bioorg. Med. Chem. Lett.,  1995, 5(10), 1061-1064.
 [http://dx.doi.org/10.1016/0960-894X(95)00166-Q]

[90]
di Salle, E.; Giudici, D.; Biagini, L.; Cominato, C.; Briatico, G.; Panzeri, A. Effects of 5 α-reductase inhibitors on intraprostatic androgens in the rat. J. Steroid Biochem. Mol. Biol.,  1995, 53(1-6), 381-385.
 [http://dx.doi.org/10.1016/0960-0760(95)00083-C] [PMID:  7626485]

[91]
Di Salle, E.; Briatico, G.; Giudici, D.; Ornati, G.; Zaccheo, T.; Buzzetti, F.; Nesi, M.; Panzeri, A. Novel aromatase and 5 α-reductase inhibitors. J. Steroid Biochem. Mol. Biol.,  1994, 49(4-6), 289-294.
 [http://dx.doi.org/10.1016/0960-0760(94)90270-4] [PMID:  8043491]

[92]
Labrie, F.; Merand, Y.M.; Singh, S.M. Inhibitors of testosterone 5α-reductase activity. WO1993023053A1, 1993.

[93]
Giudici, D.; Briatico, G.; Cominato, C.; Zaccheo, T.; Iehlè, C.; Nesi, M.; Panzeri, A.; di Salle, E. FCE 28260, a new 5 α-reductase inhibitor: In vitro and in vivo effects. J. Steroid Biochem. Mol. Biol.,  1996, 58(3), 299-305.
 [http://dx.doi.org/10.1016/0960-0760(96)00040-4] [PMID:  8836165]

[94]
Häusler, A.; Allegrini, P.R.; Biollaz, M.; Batzl, C.; Scheidegger, E.; Bhatnagar, A.S. CGP 53153: A new potent inhibitor of 5α-reductase. J. Steroid Biochem. Mol. Biol.,  1996, 57(3-4), 187-195.
 [http://dx.doi.org/10.1016/0960-0760(95)00260-X] [PMID:  8645628]

[95]
Ishibashi, K.; Kurata, H.; Hamada, T.; Horikoshi, H.; Kojima, K. Synthesis and testosterone 5α-reductase inhibitory activity of 11-substituted 4-aza-5α-androstane compounds. Eur. J. Med. Chem.,  1996, 31(9), 675-681.
 [http://dx.doi.org/10.1016/0223-5234(96)85876-4]

[96]
Tolman, R.L.; Sahoo, S.P.; Bakshi, R.K.; Gratale, D.; Patel, G.; Patel, S.; Toney, J.; Chang, B.; Harris, G.S. 4-Methyl-3-oxo-4-aza-5α-androst-1-ene-17β-N-aryl-carboxamides: An approach to combined androgen blockade [5α-reductase inhibition with androgen receptor binding in vitro]. J. Steroid Biochem. Mol. Biol.,  1997, 60(5-6), 303-309.
 [http://dx.doi.org/10.1016/S0960-0760(96)00199-9] [PMID:  9219921]

[97]
di Salle, E.; Giudici, D.; Radice, A.; Zaccheo, T.; Ornati, G.; Nesi, M.; Panzeri, A.; Délos, S.; Martin, P.M. PNU 157706, a novel dual type I and II 5α-reductase inhibitor. J. Steroid Biochem. Mol. Biol.,  1998, 64(3-4), 179-186.
 [http://dx.doi.org/10.1016/S0960-0760(97)00158-1] [PMID:  9605412]

[98]
Hasserodt, J.; Janda, K.D.; Lerner, R.A. A class of 4-aza-lithocholic acid-derived haptens for the generation of catalytic antibodies with steroid synthase capabilities. Bioorg. Med. Chem.,  2000, 8(5), 995-1003.
 [http://dx.doi.org/10.1016/S0968-0896(00)00036-5] [PMID:  10882011]

[99]
Moss, M.L.; Kuzmič, P.; Stuart, J.D.; Tian, G.; Peranteau, A.G.; Frye, S.V.; Kadwell, S.H.; Kost, T.A.; Overton, L.K.; Patel, I.R. Inhibition of human steroid 5α reductases type I and II by 6-aza-steroids: Structural determinants of one-step vs two-step mechanism. Biochemistry,  1996, 35(11), 3457-3464.
 [http://dx.doi.org/10.1021/bi952472+] [PMID:  8639496]

[100]
Frye, S.V.; Haffner, C.D.; Maloney, P.R.; Hiner, R.N.; Dorsey, G.F.; Noe, R.A.; Unwalla, R.J.; Batchelor, K.W.; Bramson, H.N.; Stuart, J.D.; Schweiker, S.L.; Van Arnold, J.; Bickett, D.M.; Moss, M.L.; Tian, G.; Lee, F.W.; Tippin, T.K.; James, M.K.; Grizzle, M.K.; Long, J.E.; Croom, D.K. Structure-activity relationships for inhibition of type 1 and 2 human 5 alpha-reductase and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase by 6-azaandrost-4-en-3-ones: Optimization of the C17 substituent. J. Med. Chem.,  1995, 38(14), 2621-2627.
 [http://dx.doi.org/10.1021/jm00014a015] [PMID:  7629802]
Rights & Permissions Print Cite
Explore Articles
Open Access
Open Access Articles
DOI https://dx.doi.org/10.2174/0115701808241219230923154750	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X
Letters in Drug Design & Discovery

A Review of the Azasteroid-type 5-alpha Reductase Inhibitors for the Management of Benign Prostatic Hyperplasia

Abstract Play Pause

Abstract
