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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

[ Vol. 17 , Issue. 1 ]

Author(s):

Marisa Cabeza*, Lucero Bautista, Eugene Bratoeff, Juan Soriano and Yvonne Heuze   Pages 16 - 25 ( 10 )

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.

Affiliation:

Departamento de Sistemas Biologicos y Produccion Agricola y Animal. Universidad Autonoma Metropolitana- Xochimilco, Calzada del Hueso 1100. Col. Villa Quietud, 04960 Ciudad de Mexico, Departamento de Sistemas Biologicos y Produccion Agricola y Animal. Universidad Autonoma Metropolitana- Xochimilco, Calzada del Hueso 1100. Col. Villa Quietud, 04960 Ciudad de Mexico, Departamento de Farmacia. Universidad Nacional Autonoma de Mexico, Department of Pathology, General Hospital of Mexico (SS)c, CDMX, Departamento de Sistemas Biologicos y Produccion Agricola y Animal. Universidad Autonoma Metropolitana- Xochimilco, Calzada del Hueso 1100. Col. Villa Quietud, 04960 Ciudad de Mexico

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