Androsterone 3α-ether-3β-substituted and androsterone 3β-substituted derivatives as inhibitors of type 3 17β-hydroxysteroid dehydrogenase:: Chemical synthesis and structure-activity relationship

Type 3 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) is involved in the biosynthesis of androgen testosterone. To produce potent inhibitors of this key steroidogenic enzyme, we prepared a series of androsterone (ADT) derivatives by adding a variety of substituents at position 3. The 3 beta-substituted ADT derivatives proved to be good inhibitors (IC50 = 57-147 nM) with better inhibitory activities obtained for compounds bearing a propyl, s-butyl, cyclohexylalkyl, or phenylalkyl group. With an IC50 value of 57 nM, the 3 beta-phenylmethyl-ADT was 6-fold more potent than ADT, the lead compound, and 13-fold more potent than 4-androstene-3,17-dione, the natural enzyme substrate used itself as inhibitor. The 3 alpha-ether-3 beta-substituted ADT derivatives had a lower inhibitory activity compared to the 3 beta-substituted ADT analogues except for the 3 beta-phenylethyl-3 alpha-methl-O-ADT (IC50 = 73 nM), which proved to be a more potent inhibitor than 3 beta-phenylethyl-ADT (IC50 = 99 nM). The results of our study identified potent type 3 17 beta-HSD inhibitors for potential use in the treatment of androgen-sensitive diseases.