Design, Synthesis, and Biological Characterization of Orally Active 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibitors Targeting the Prevention of Osteoporosis

Research output: Contribution to journalResearch articleContributedpeer-review


  • Ahmed S Abdelsamie - (Author)
  • Mohamed Salah - (Author)
  • Lorenz Siebenbürger - (Author)
  • Ahmed Merabet - (Author)
  • Claudia Scheuer - (Author)
  • Martin Frotscher - (Author)
  • Sebastian T Müller - (Author)
  • Oliver Zierau - , Environmental Monitoring and Endocrinology (Research Group) (Author)
  • Günter Vollmer - (Author)
  • Michael D Menger - (Author)
  • Matthias W Laschke - (Author)
  • Chris J van Koppen - (Author)
  • Sandrine Marchais-Oberwinkler - (Author)
  • Rolf W Hartmann - (Author)


Osteoporosis 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.


Original languageEnglish
Pages (from-to)7289-7301
Number of pages13
JournalJournal of medicinal chemistry
Issue number15
Publication statusPublished - 8 Aug 2019

External IDs

Scopus 85067211098



  • Administration, Oral, Animals, Bone Density Conservation Agents/administration & dosage, Drug Delivery Systems/methods, Drug Design, Enzyme Inhibitors/administration & dosage, Estradiol Dehydrogenases/antagonists & inhibitors, Female, Humans, Mice, Mice, Inbred C57BL, Osteoporosis/enzymology, Rats, Rats, Wistar