| Summary: | 17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed at high levels in testes and seminal vesicles; it is also present in prostate tissue and involved in gonadal and non-gonadal testosterone biosynthesis. The enzyme is membrane-bound, and a crystal structure is not yet available. Selective aryl benzylamine-based inhibitors were designed and synthesised as potential agents for prostate cancer therapeutics through structure-based design, using a previously built homology model with docking studies. Potent, selective, low nanomolar IC<sub>50</sub> 17β-HSD3 inhibitors were discovered using <i>N</i>-(2-([2-(4-chlorophenoxy)phenylamino]methyl)phenyl)acetamide (<b>1</b>). The most potent compounds have IC<sub>50</sub> values of approximately 75 nM. Compound <b>29</b>, <i>N</i>-[2-(1-Acetylpiperidin-4-ylamino)benzyl]-<i>N</i>-[2-(4-chlorophenoxy)phenyl]acetamide, has an IC<sub>50</sub> of 76 nM, while compound <b>30</b>, <i>N</i>-(2-(1-[2-(4-chlorophenoxy)-phenylamino]ethyl)phenyl)acetamide, has an IC<sub>50</sub> of 74 nM. Racemic <i>C</i>-allyl derivative <b>26</b> (IC<sub>50</sub> of 520 nM) was easily formed from <b>1</b> in good yield and, to determine binding directionality, its enantiomers were separated by chiral chromatography. Absolute configuration was determined using single crystal X-ray crystallography. Only the <i>S</i>-(+)-enantiomer (<b>32</b>) was active with an IC<sub>50</sub> of 370 nM. Binding directionality was predictable through our in silico docking studies, giving confidence to our model. Importantly, all novel inhibitors are selective over the type 2 isozyme of 17β-HSD2 and show <20% inhibition when tested at 10 µM. Lead compounds from this series are worthy of further optimisation and development as inhibitors of testosterone production by 17β-HSD3 and as inhibitors of prostate cancer cell growth.
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