Novel 5α-Reductase Inhibitors: Synthesis, Structure-Activity Studies, and Pharmacokinetic Profile of Phenoxybenzoylphenyl Acetic Acids

The study synthesized and evaluated novel substituted benzoyl benzoic acids and phenylacetic acids for their ability to inhibit rat and human steroid 5α-reductase isozymes 1 and 2. The compounds were found to be potent and selective inhibitors of the human type 2 enzyme, with IC(50) values in the nanomolar range. Phenylacetic acid derivatives were more effective than benzoic acids, with the strongest inhibitor being a brominated phenoxy compound (compound 12) with an IC(50) of 5 nM, comparable to finasteride. Compound 12 demonstrated good oral absorption, high bioavailability, and a biological half-life of 5.5 hours in rats, indicating its potential as a candidate for clinical evaluation.