jm9b00932_si_002.csv (2.59 kB)
Download fileDesign, Synthesis, and Biological Characterization of Orally Active 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibitors Targeting the Prevention of Osteoporosis
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posted on 2019-07-25, 13:37 authored by Ahmed
S. Abdelsamie, Mohamed Salah, Lorenz Siebenbürger, Ahmed Merabet, Claudia Scheuer, Martin Frotscher, Sebastian T. Müller, Oliver Zierau, Günter Vollmer, Michael D. Menger, Matthias W. Laschke, Chris J. van Koppen, Sandrine Marchais-Oberwinkler, Rolf W. HartmannOsteoporosis is predominantly treated
with drugs that inhibit further
bone resorption due to estrogen deficiency. Yet, osteoporosis drugs
that not only inhibit bone resorption but also stimulate bone formation,
such as potentially inhibitors of 17β-hydroxysteroid dehydrogenase
type 2 (17β-HSD2), may be more efficacious in the treatment
of osteoporosis. Blockade of 17β-HSD2 is thought to increase
intracellular estradiol and testosterone in bone, thereby inhibiting
bone resorption by osteoclasts and stimulating bone formation by osteoblasts,
respectively. We here describe the design, synthesis, and biological
characterization of a novel bicyclic-substituted hydroxyphenylmethanone
17β-HSD2 inhibitor (compound 24). Compound 24 is a nanomolar potent inhibitor of human 17β-HSD2
(IC50 of 6.1 nM) and rodent 17β-HSD2 with low in
vitro cellular toxicity, devoid of detectable estrogen receptor α
affinity, displays high aqueous solubility and in vitro metabolic
stability, and has an excellent oral pharmacokinetic profile for testing
in a rat osteoporosis model. Administration of 24 in
a rat osteoporosis model demonstrates its bone-sparing efficacy.