Recent Advances in Drug Design and Drug Discovery for Androgen- Dependent Diseases

Abstract

This article summarizes the importance of different targets such as 5α-reductase, 17β-HSD, CYP17A, androgen receptor and protein kinase A for the treatment of prostate cancer and benign prostatic hyperplasia. It is a well known fact that dihydrotestosterone (DHT) is associated with the development of androgen-dependent afflictions. At the present time, several research groups are attempting to develop new steroidal and non-steroidal molecules with the purpose of inhibiting the synthesis and biological response of DHT. This review also discusses the most recent studies reported in the literature that describe the therapeutic potential of novel compounds, as well as the new drugs, principally inhibitors of 5α-reductase.

Evaluation of A-ring fused pyridine d-modified androstane derivatives for antiproliferative and aldo–keto reductase 1C3 inhibitory activity

“…5 Steroidal compounds such as abiraterone target androgen biosynthesis through inhibition of 17α-hydroxylase/C 17,20 -lyase (CYP17A1), 6 while anti-androgens such as cyproterone acetate 7 or the non-steroid enzalutamide 8 target androgen recep-tor (AR) signaling. 9 CYP17A1 is a dual-function cytochrome P450 enzyme that is essential for the first steps of androgen biosynthesis; it catalyzes 17α-hydroxylation of pregnenolone and progesterone and via 17,20-lyase activity conversion to dehydroepiandrosterone (DHEA), a precursor of testosterone and estrogen. 6 Based on X-ray crystal structures, abiraterone binds with high affinity to the active site of CYP17A1 by coordinating the P450 heme iron through its pyridine nitrogen.…”

Deleterious effect of short-term gavage of an ethanol extract of cogon grass (Imperata cylindrica L.) roots on testis and epididymal sperm quality

“…The testes, epididymis, seminal vesicles, and ventral prostate are androgen-dependent organs, relying on testosterone for their function and growth [ 23 ]. Therefore, the decrease in the testis-BW ratio (index) and seminal vesicle BW ratio observed in this study may indicate decreased androgen bioavailability.…”

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

“…Even in castrated patients, androgen ligands may still be synthesized by other pathways or de novo. Both ketoconazole and abiraterone are inhibitors of CYP17A [566,567] (Figure 6A), a hydroxylase/lyase involved in steroid synthesis that appears to be responsible for continual androgen synthesis in castrated patients [568]. Ketoconazole is significantly more toxic that abiraterone [569,570].…”