Endocrine Abstracts

It is well-known that the increase of intraprostatic levels of 5α-dihydrotestosterone is related to the development of prostatic pathologies such as benign prostatic hyperplasia and prostate cancer. So finasteride and dutasteride-based therapies have been used to improve these diseases. These drugs are potent inhibitors of the enzyme 5α-reductase, which is found in the androgen-dependent tissues. This enzyme is responsible for converting testosterone into dihydrotestosterone in these tissues. This study aimed to identify the effect of new pregnane (2-8) analogs as inhibitors of 5α-reductase activity. The action of these steroidal derivatives was compared with that of finasteride. Two different experiments were performed: in vivo and in vitro. In in vitro experiments, we separately incubated derivatives 2-8 in the presence of radiolabeled testosterone, a membrane fraction of the human prostate as a source of 5α-reductase and NADPH. In addition, products 2-8 were also evaluated in testosterone-treated neutered male hamsters. After six days of treatment, the hamsters were sacrificed, and the weight of the prostate was determined. Finasteride was used as a reference compound in both in vitro and in vivo experiments. The results indicated that steroids 2-8 inhibited 5α-reductase activity showing 6-8 higher potency, with IC₅₀ values of: 0.169, 0.105, and 0.155 nM, respectively. These IC₅₀ values were lower than those determined for the reference compound finasteride (IC₅₀ = 8.5 nM). However, pharmacological experiments demonstrated a non-significant difference between the weight of the prostate in castrated hamsters treated with testosterone to those treated with testosterone plus each of the novel steroids. At the same time, testosterone plus finasteride treatment effectively decreased the weight of this gland. In conclusion, derivatives 6-8 were more potent than finasteride to blockade in vitro dihydrotestosterone formation. Nevertheless, their lack of efficacy for decreasing the weight of the prostate could be explained based on the pharmacokinetic processes undergoing these steroids.

Table 1. A series of pregnane derivatives (2-3) with a 17-N-cyclohexylcarboxamide residue (5-8) were evaluated as blockers of 5α-reductase type 2 (SRDA2) activity. The figure shows the 50% (IC₅₀ value) inhibition of enzyme produced by 2-8. Finasteride was used as the reference compound.