E-Ring Modified Steroids as Novel Potent Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1

17β-Hydroxysteroid dehydrogenases (17β-HSDs) are an important class of steroidogenic enzymes that regulate the bioavailability of active estrogens and androgens and are as yet a relatively unexploited therapeutic target. Based on our investigations and those of others, E-ring modified steroids were identified as a useful template for the design of inhibitors of 17β-HSD type 1, an enzyme involved in the conversion of estrone into estradiol. The synthesis and biological evaluation of a new series of N- and C-substituted 1,3,5(10)-estratrien-[17,16-c]-pyrazoles and the corresponding SAR are discussed. Among the N-alkylated analogues, the most potent inhibitor was the 1‘-methoxyethyl derivative, <BO>41</BO>, with an IC<INF>50</INF> of 530 nM in T47-D human breast cancer cells. The X-ray crystal structure of the 1‘-isobutyl derivative, <BO>37</BO>, was determined. Further optimization of the template using parallel synthesis resulted in a library of C5‘-linked amides from which <BO>73</BO> emerged. This pyridylethyl amide had an IC<INF>50</INF> of 300 nM and its activity, with that of <BO>41</BO>, suggests the importance of hydrogen bond acceptor groups in the pyrazole side chain. Both <BO>41</BO> and <BO>73</BO> displayed selectivity over 17β-HSD type 2, and preliminary investigations showed <BO>41</BO> to be nonestrogenic in vitro in a luciferase reporter gene assay in contrast to the parent pyrazole <BO>25</BO>. Molecular modeling studies, which support these findings, and a QSAR, the predictive power of which was demonstrated, are also presented.