Cyclohex‐1‐ene Carboxylic Acids: Synthesis and Biological Evaluation of Novel Inhibitors of Human 5α Reductase

Abstract

In search of novel nonsteroidal mimics of steroidal inhibitors of 5 alpha reductase, 4-(2-phenylethyl)cyclohex-1-ene carboxylic acids 1-5 were synthesized with different substituents in para position of the phenyl ring (1: N, N-diisopropylcarbamoyl, 2: phenyl, 3: phenoxy, 4: benzoyl, and 5: benzyl). The principal synthetic approach for the desired compounds consisted of a Wittig olefination between 1, 4-dioxaspiro [4.5]-decane-8-carbaldehyde (4g and the appropriate phosphonium salts. The compounds were tested for inhibition of human 5 alpha reductase isozymes 1 and 2 using DU 145 cells and preparations from prostatic tissue, respectively. They turned out to be good inhibitors of the prostatic isozyme 2 with compound 1 being the most potent one (IC(50) = 760 nM). Isozyme 1 was only slightly inhibited. It is concluded that the novel structures are appropriate for being further optimized, aiming at the development of a novel drug for the treatment of benign prostatic hyperplasia.

Pharmacophore and Atom Based 3D QSAR Studies on the Novel 5-Alpha-Reductase Inhibitors

“…14 Thus, nonsteroidal inhibitors are developed to overcome these adverse effects, but the activity of non-steroidal molecules as 5aR inhibition remain less. [15][16][17][18] Apart from this, there are only a few drugs available to treat prostate diseases and existing drugs are becoming resistant. So, there is an urgent need for a drug which is highly specific and less toxic.…”