Type-1 steroid 5 alpha-reductase is functionally active in the hair follicle as evidenced by new selective inhibitors of either type-1 or type-2 human steroid 5 alpha-reductase

Abstract

Steroid 5 alpha-reductase catalyzes the reduction of testosterone (T) into the very potent androgen dihydrotestosterone (DHT). The different tissue expression patterns of the two isoforms of 5 alpha-reductase, namely type-1 and type-2 5 alpha-reductase (5 alpha-R1 and 5 alpha-R2, respectively), have prompted studies directed towards the synthesis of selective 5 alpha-R1 or 5 alpha-R2 inhibitors. In this present work, we have performed a structure/activity study on the inhibitory potential of indole carboxylic acids against hair follicle 5 alpha-reductase activity. We have demonstrated that this class of molecules were potent inhibitors of either 5 alpha-R1 or 5 alpha-R2 or both depending on (i) substituents in positions 4, 5 or 6 and (ii) the presence of a free carboxylic group. We have also found that only 5 alpha-R1 or 5 alpha-R1/R2 inhibitors were able to inhibit 5 alpha-reductase activity in plucked hairs from female volunteers or in freshly isolated female hair follicles, selective 5 alpha-R2 inhibitors being inactive.