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 (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.