synthesis of novel androstane-n-cyclohexyl-17-carboxamides, and their effect on the 5α-reductase isoform 2, the androgen receptor, and androgen-dependent glands

Background: benign prostatic hyperplasia (bph), and prostate cancer (pca) are androgendependent diseases. ppca is associated with excessive signalling of the androgen receptor (ar) due to the binding of 5α-dihydrotestosterone (5α-dht) and testosterone (t). bph is related to high levels of 5α-dht, biosynthesized from t by 5α-reductase (5rd5a). the inhibition of 5rd5a and the blockage of ar are targets for their treatment. in this study, the synthesis and determination of biological activity of the new n-cyclohexyl-3β-hydroxyandrosta-5,16- diene-17-carboxamide (6), n-cyclohexyl-3-oxoandrosta-4,6,16-triene-17-carboxamide (7), and n-cyclohexyl-3-oxoandrosta-4,16-diene-17-carboxamide (8) were carried out to find new drugs to improve these afflictions. methods: the synthesis of 6 to 8 was confirmed by spectroscopic and spectrometric analyses. competitive binding assays determined the affinity of 6 to 8 to the ar. the inhibitory activity of 5rd5a isoform 2 (5rd5a2) (ic50) was established by the conversion of [3h]-t to [3h]-5α-dht and it was compared with finasteride (fin). the pharmacological effect of 6 to 8 was determined on the weight of the prostate and seminal vesicles glands of castrated hamsters treated with t, and on the diameter size of their flank organs. results: compounds 7 and 8 bound lightly (ca. 15 %) to ar. comparing to fin (ic50 = 8.5 nm), 6 to 8 (ic50 = 0.169, 0.105 and 0.155 nm, respectively) showed higher potency as inhibitors of 5rd5a2. compound 6 decreased the prostate and seminal vesicles weight, as well as the hamsters’ diameter flank organs. however, 7 only decreased the diameter of flank organs. surprisingly, 8 increased these pharmacological parameters. conclusion: androstane-17-caboxamide 6 is a 5rd5a2 inhibitor that reduces the weight of androgen-dependent glands such as the prostate, suggesting it could be a lead for new drugs to treat bph and pca.