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

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

Journal Name: Current Enzyme Inhibition

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Background: 5α-Reductase inhibitors have proven useful for the treatment of prostate diseases, which can result from the unregulated activity of the 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 on the effect of current drugs.

Methods: In vitro effect of compounds 1-4 on the activity of the human prostate enzyme, 5α-reductase, was determined 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 17β-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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(E-pub Ahead of Print)
DOI: 10.2174/1573408016999200928153524
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