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Current Enzyme Inhibition

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

DOI: 10.2174/1573408015666191105144355

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Effect of Pregnenolone Derivatives on the Selective Inhibition of 5α-Reductase 2 Activity

Page: [179 - 189] Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Background: Benign prostatic hyperplasia and prostate cancer are androgen-dependent diseases, and dihydrotestosterone (DHT), a 5α-reduced metabolite of testosterone (T), has been implicated as a causative factor in the progression of these diseases. The 5α-reductase enzyme (5α-R) converts T to DHT, which is responsible for increasing cell proliferation, and hence inhibition of this enzyme could lead to potential treatments for these afflictions.

Objective: This study focused on evaluating the biological activity of three series of pregnenolone derivatives as inhibitors of 5α-R and as antiandrogens on androgen-dependent glands.

Methods: To determine the biological activity of these compounds, we evaluated the effect of each one on suppressing the activity of both types of isozymes of 5α-R (1 and 2) by 50% (IC50). Using animal studies, we assessed the effect of these derivatives on the weight of the prostate, seminal vesicles, and diameter of the flank organs of castrated hamsters previously dosed with 1 mg/Kg T.

Results: In vitro experiments showed that derivatives 1f, 2b, and 3d were very effective inhibitors of the activity of 5α-R2, showing IC50 values of 21.8, 20, and 15 nM, respectively. Derivatives 2b and 3b showed a lower inhibition effect on 5α-R1.

The data also indicated that derivatives 2b, 1f, 3b, and 3d were very active in reducing prostate weight in the hamster model of benign prostatic hyperplasia.

Discussion: Pharmacological experiments showed that pregnenolone derivatives possess an antiandrogenic effect because of the inhibition of DHT production in androgen-dependent glands.

Conclusion: The pregnenolone derivatives studied suppressed type 2 5α-reductase activity and because of this, the weight and dimension of androgen-dependent organs were decreased.

Keywords: Electronegativity effect, flank organ test, pregnenolone derivatives, prostate, seminal vesicles, specificity by 5α- reductase 2, structure-activity improvement, type 2 5α-reductase.

Graphical Abstract

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