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Current Enzyme Inhibition

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ISSN (Print): 1573-4080
ISSN (Online): 1875-6662

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Research Article

In vitro and In vivo Effects of 17β-N-(4-phenylcarbamoyl) androst-4-en-3- one Derivatives as 5a-reductase Inhibitors on Androgen-dependent Glands

Author(s): Marisa Cabeza*, Lucero Bautista, Eugene Bratoeff, Juan Soriano and Yvonne Heuze

Volume 17, Issue 1, 2021

Published on: 28 September, 2020

Page: [16 - 25] Pages: 10

DOI: 10.2174/1573408016999200928153524

Price: $65

Abstract

Introduction: 5α-reductase inhibitors have been proven useful for the treatment of prostate diseases, which can be due to the unregulated activity of 5α-reductase enzyme. This study was focused on determining the activity of four different derivatives of 17β-phenyl carbamoyl-androst-4-en-3-one 1–4 as inhibitors of 5α-reductase (5RD5A), to improve the effects of current drugs.

Methods: In vitro effect of compounds 1-4 on the activity of the human prostate enzyme, 5α-reductase, was determined by measuring IC50 values, the concentration of a compound that inhibits the activity of 5RD5A2 by 50%. In vivo, the pharmacological effects of compounds 1-4 were identified in a hamster model of prostate hypertrophy.

Results: The steroidal 17β-carboxamides 1, 3, and 4 (IC50 = 5±0.5, 0.112±0.045, 0.167±0.056 nM) significantly inhibited the in vitro activity of the 5RD5A2 enzyme with higher potency than finasteride, which is a drug known as a specific 5RD5A2 inhibitor (IC50 = 8.5±0.3 nM). Compounds 1, 3, and 4 were more potent than finasteride to decrease the size of hamster flank organs in castrated animals treated with testosterone. Also, compounds 1-4 were more effective than finasteride itself to reduce the weight of the prostate in the hamster model, without producing toxicological effects during the six days of treatment.

Conclusion: In conclusion, the steroidal 17 β-carboxamides 1-4 were suitable inhibitors of human 5RD5A2 activity, in addition to being able to reduce prostate weight without causing toxicity. These steroids could, therefore, have promising therapeutic potential for the treatment of benign prostatic hyperplasia.

Keywords: Type 2 5α-reductase, prostate, 17β-phenylcarbamoyl-androst-4-en-3-one derivatives, benign prostatic hyperplasia, prostate cancer, testosterone, dihydrotestosterone.

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[1]
Russell, D.W.; Wilson, J.D. Steroid 5 α-reductase: Two genes/two enzymes. Annu. Rev. Biochem., 1994, 63(1), 25-61.
[http://dx.doi.org/10.1146/annurev.bi.63.070194.000325] [PMID: 7979239]
[2]
Jenkins, E.P.; Andersson, S.; Imperato-McGinley, J.; Wilson, J.D.; Russell, D.W. Genetic and pharmacological evidence for more than one human steroid 5 α-reductase. J. Clin. Invest., 1992, 89(1), 293-300.
[http://dx.doi.org/10.1172/JCI115574] [PMID: 1345916]
[3]
Marberger, M. Drug Insight: 5α-reductase inhibitors for the treatment of benign prostatic hyperplasia. Nat. Clin. Pract. Urol., 2006, 3(9), 495-503.
[http://dx.doi.org/10.1038/ncpuro0577] [PMID: 16964191]
[4]
Thomas, L.N.; Lazier, C.B.; Gupta, R.; Norman, R.W.; Troyer, D.A.; O’Brien, S.P.; Rittmaster, R.S. Differential alterations in 5α-reductase type 1 and type 2 levels during development and progression of prostate cancer. Prostate, 2005, 63(3), 231-239.
[http://dx.doi.org/10.1002/pros.20188] [PMID: 15538746]
[5]
Liang, T.; Heiss, C.E.; Cheung, A.H.; Reynolds, G.F.; Rasmusson, G.H. 4-Azasteroidal 5 α-reductase inhibitors without affinity for the androgen receptor. J. Biol. Chem., 1984, 259(2), 734-739.
[PMID: 6693392]
[6]
Aggarwal, S.; Thareja, S.; Bhardwaj, T.R.; Kumar, M. Self-organizing molecular field analysis on pregnane derivatives as human steroidal 5α-reductase inhibitors. Steroids, 2010, 75(6), 411-418.
[http://dx.doi.org/10.1016/j.steroids.2010.02.005] [PMID: 20170668]
[7]
Marchetti, F.; Guarna, A. Novel inhibitors of 5α-reductase. Expert Opin. Ther. Pat., 2002, 12(2), 201-215.
[http://dx.doi.org/10.1517/13543776.12.2.201]
[8]
Titus, M.A.; Li, Y.; Kozyreva, O.G.; Maher, V.; Godoy, A.; Smith, G.J.; Mohler, J.L. 5α-reductase type 3 enzyme in benign and malignant prostate. Prostate, 2014, 74(3), 235-249.
[http://dx.doi.org/10.1002/pros.22745] [PMID: 24150795]
[9]
Cabeza, M.; Bratoeff, E.; Heuze, I.; Rojas, A.; Terán, N.; Ochoa, M.; Ramírez-Apan, T.; Ramírez, E.; Pérez, V.; Gracia, I. New progesterone derivatives as inhibitors of 5α-reductase enzyme and prostate cancer cell growth. J. Enzyme Inhib. Med. Chem., 2006, 21(4), 371-378.
[http://dx.doi.org/10.1080/14756360600748474] [PMID: 17059168]
[10]
Bratoeff, E.; Cabeza, M.; Pérez-Ornelas, V.; Recillas, S.; Heuze, I. In vivo and in vitro effect of novel 4,16-pregnadiene-6,20-dione derivatives, as 5α-reductase inhibitors. J. Steroid Biochem. Mol. Biol., 2008, 111(3-5), 275-281.
[http://dx.doi.org/10.1016/j.jsbmb.2008.06.014] [PMID: 18644453]
[11]
Cortés-Benítez, F.; Cabeza, M.; Ramírez-Apan, M.T.; Álvarez-Manrique, B.; Bratoeff, E. Synthesis of 17β-N-arylcarbamoyland-rost-4-en-3-one derivatives and their anti-proliferative effect on human androgen-sensitive LNCaP cell line. Eur. J. Med. Chem., 2016, 121, 737-746.
[http://dx.doi.org/10.1016/j.ejmech.2016.05.059] [PMID: 27423983]
[12]
Trapani, G.; Dazzi, L.; Pisu, M.G.; Reho, A.; Seu, E.; Biggio, G. A rapid method for obtaining finasteride, a 5α-reductase inhibitor, from commercial tablets. Brain Res. Brain Res. Protoc., 2002, 9(2), 130-134.
[http://dx.doi.org/10.1016/S1385-299X(02)00146-0] [PMID: 12034332]
[13]
Bradford, M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 1976, 72(1–2), 248-254.
[http://dx.doi.org/10.1016/0003-2697(76)90527-3] [PMID: 942051]
[14]
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]
[15]
Levy, M.A.; Brandt, M.; Greway, A.T. Mechanistic studies with solubilized rat liver steroid 5 α-reductase: Elucidation of the kinetic mechanism. Biochemistry, 1990, 29(11), 2808-2815.
[http://dx.doi.org/10.1021/bi00463a025] [PMID: 2140700]
[16]
Altschul, S.F.; Wootton, J.C.; Gertz, E.M.; Agarwala, R.; Morgulis, A.; Schäffer, A.A.; Yu, Y.K. Protein database searches using compositionally adjusted substitution matrices. FEBS J., 2005, 272(20), 5101-5109.
[http://dx.doi.org/10.1111/j.1742-4658.2005.04945.x] [PMID: 16218944]
[17]
Bruchovsky, N.; Wilson, J.D. The conversion of testosterone to 5-α-androstan-17-β-ol-3-one by rat prostate in vivo and in vitro. J. Biol. Chem., 1968, 243(8), 2012-2021.
[PMID: 4384673]
[18]
Cabeza, M.; Flores, E.; Heuze, I.; Sánchez, M.; Bratoeff, E.; Ramírez, E.; Francolugo, V.A. Novel 17 substituted pregnadiene derivatives as 5 α-reductase inhibitors and their binding affinity for the androgen receptor. Chem. Pharm. Bull. (Tokyo), 2004, 52(5), 535-539.
[http://dx.doi.org/10.1248/cpb.52.535] [PMID: 15133203]
[19]
Mukherjee, A.; Kirkovsky, L.I.; Kimura, Y.; Marvel, M.M.; Miller, D.D.; Dalton, J.T. Affinity labeling of the androgen receptor with nonsteroidal chemoaffinity ligands. Biochem. Pharmacol., 1999, 58(8), 1259-1267.
[http://dx.doi.org/10.1016/S0006-2952(99)00218-X] [PMID: 10487527]
[20]
Takayasu, S.; Adachi, K. The intranuclear binding of 17 beta-hydroxy-5 α-androstan-3-one and testosterone by hamster sebaceous glands. Endocrinology, 1975, 96(2), 525-529.
[http://dx.doi.org/10.1210/endo-96-2-525] [PMID: 163188]
[21]
Takayasu, S.; Adachi, K. The In vivo and in vitro conversion of testosterone to 17 -hydroxy-5 -adrosten-3-one (dihydrotestosterone) by the sebaceous gland of hamsters. Endocrinology, 1972, 90(1), 73-80.
[http://dx.doi.org/10.1210/endo-90-1-73] [PMID: 4400287]
[22]
Vermorken, A.J.M.; Goos, C.M.A.A.; Wirtz, P. Evaluation of the hamster flank organ test for the screening of anti-androgens. Br. J. Dermatol., 1982, 106(1), 99-101.
[http://dx.doi.org/10.1111/j.1365-2133.1982.tb00908.x] [PMID: 7059508]
[23]
Hsia, S.L.; Voigt, W. Inhibition of dihydrotestosterone formation: an effective means of blocking androgen action in hamster sebaceous gland. J. Invest. Dermatol., 1974, 62(3), 224-227.
[http://dx.doi.org/10.1111/1523-1747.ep12676791] [PMID: 4361987]
[24]
Bratoeff, E.; Sainz, T.; Cabeza, M.; Heuze, I.; Recillas, S.; Pérez, V.; Rodríguez, C.; Segura, T.; Gonzáles, J.; Ramírez, E. Steroids with a carbamate function at C-17, a novel class of inhibitors for human and hamster steroid 5α-reductase. J. Steroid Biochem. Mol. Biol., 2007, 107(1-2), 48-56.
[http://dx.doi.org/10.1016/j.jsbmb.2007.03.038] [PMID: 17629476]
[25]
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]

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