Impact of androstane A- and D-ring inversion on 17β-hydroxysteroid dehydrogenase type 3 inhibitory activity, androgenic effect and metabolic stability.

Cortés-Benítez F, Roy J, Maltais R et al.

Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec – Research Center, Québec, Québec, Canada; Department of Pharmacy, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico.

Bioorganic & medicinal chemistry. Feb 2017.

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a major player in human endocrinology, being one of the most important enzymes involved in testosterone production. To capitalize on the discovery of RM-532-105, a steroidal 17β-HSD3 inhibitor, we explored the effect of its backbone configuration on inhibitory activity, androgenic profile, and metabolic stability. Two modifications that greatly alter the natural shape of steroids, i.e. inversion of the methyl on carbon 13 (13α-CH3 instead of 13β-CH3) and inversion of the hydrogen on carbon 5 (5β-H instead of 5α-H), were tested after the syntheses in 6 steps of 2 isomeric forms (5α/13α-RM-532-105 (6a) and 5β/13β-RM-532-105 (6b), respectively) of the 17β-HSD3 inhibitor RM-532-105 (5α/13β-configurations). For compound 6b, a cis/trans junction of the A/B rings did not significantly alter the inhibitory activity on 17β-HSD3 (IC50=0.15μM) as well as the liver microsomal stability (16.6% of 6b remaining after 1h incubation) compared to RM-532-105 (IC50=0.11μM and 14.1% remaining). In contrast, a trans/cis junction of C/D rings reduced the inhibitory activity on 17β-HSD3 (IC50=1.09μM) but increased the metabolic stability with 29.4% of compound 6a remaining after incubation. The structural modifications represented by compounds 6a and 6b did not change the non-androgenicity profile of an androsterone derivative such as RM-532-105, but slightly increased its cytotoxic activity.


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