3β-hydroxysteroid dehydrogenase/isomerase type 1 (3β-HSD1) is an important enzyme in the steroid biosynthesis of estradiol and progesterone in human placenta. It has two human isoforms, 3β-HSD1 (in placenta, mammary gland, breast tumors) and 3β-HSD2 (in adrenal, ovary, testis). By exploiting the key differences in amino acid sequences of 3β-HSD1 and 3β-HSD2, we have designed a selective inhibitor that can potentially control estradiol levels in the fetal-placental unit near term to prevent premature labor in humans without affecting adrenal or ovarian function. 2,16-dicyano-4,5-epoxy-androstane-3,17-dione was synthesized in a 4-step procedure from androstendione. Autodock 4.0 was used to design the inhibitor and for further analysis of the inhibitor-enzyme interaction. In enzyme inhibition studies, 2,16-dicyano-4,5-epoxy-androstane-3,17-dione competitively inhibited 3β-HSD1 with a Ki value of 4.7 μM and noncompetitively inhibited 3β-HSD2 with a Ki value of 30.7 μM. At therapeutic serum levels of the inhibitor (10 µM, 2 × Ki), 3β-HSD1 will be almost completely inhibited in placenta, while 3β-HSD2 will not be significantly inhibited. After additional studies to fully characterize the effectiveness of this novel compound, 2,16-dicyano-4,5-epoxy-androstane-3,17-dione may evolve into a therapeutic agent used to prevent premature labor.

Development of a selective inhibitor for human 3β-hydroxysteroid dehydrogenase 1 (3βHSD1)

251st National Meeting (2016)

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