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

[ Vol. 15 , Issue. 3 ]

Author(s):

Marisa Cabeza*, Lucero Bautista, Eugene Bratoeff , Juan Soriano and Yvonne Heuze   Pages 179 - 189 ( 11 )

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.

Affiliation:

Departamento de Sistemas Biologicos y Produccion Agrícola y Animal, Universidad Autonoma Metropolitana- Xochimilco, Calzada del Hueso 1100. Col, Villa Quietud, 04960 Ciudad de Mexico, Departamento de Sistemas Biologicos y Produccion Agrícola 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, Ciudad de Mexico, Departamento de Patología, Hospital General de Mexico, Dr. Balmis 148, Ciudad de Mexico, Departamento de Sistemas Biologicos y Produccion Agrícola y Animal, Universidad Autonoma Metropolitana- Xochimilco, Calzada del Hueso 1100. Col, Villa Quietud, 04960 Ciudad de Mexico

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