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

In search of novel nonsteroidal mimics of steroidal inhibitors of 5α 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 5α 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 (IC50 = 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.