Abstract
17β-Hydroxysteroid dehydrogenase 2 (17β-HSD2) catalyzes the inactivation of estradiol into estrone. This enzyme is expressed only in a few tissues, and therefore its inhibition is considered as a treatment option for osteoporosis to ameliorate estrogen deficiency. In this study, ligand-based pharmacophore models for 17β-HSD2 inhibitors were constructed and employed for virtual screening. From the virtual screening hits, 29 substances were evaluated in vitro for 17β-HSD2 inhibition. Seven compounds inhibited 17β-HSD2 with low micromolar IC50 values. To investigate structure–activity relationships (SAR), 30 more derivatives of the original hits were tested. The three most potent hits, 12, 22, and 15, had IC50 values of 240 nM, 1 μM, and 1.5 μM, respectively. All but 1 of the 13 identified inhibitors were selective over 17β-HSD1, the enzyme catalyzing conversion of estrone into estradiol. Three of the new, small, synthetic 17β-HSD2 inhibitors showed acceptable selectivity over other related HSDs, and six of them did not affect other HSDs.
Highlights
The worldwide prevalence of osteoporosis is high: already in 2006 it was estimated that over 200 million people suffered from this disease.[1]
Bone density is a result of the balance between osteoblast and osteoclast activities: while osteoblasts are responsible for the formation and mineralization of the bone, osteoclasts play an important role in bone degradation
We report the development of a pharmacophore model for 17β-HSD2 inhibitors and its use in a virtual screening campaign
Summary
The worldwide prevalence of osteoporosis is high: already in 2006 it was estimated that over 200 million people suffered from this disease.[1]. It has been shown that both estradiol and testosterone inhibit bone degradation, thereby providing an explanation for the age-related onset of osteoporosis.[6]
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