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Open Access Green as soon as Postprint is submitted to ZB.
Structural optimization of 2,5-tiophene amides as highly potent and selective 17β-hydroxysteroid dehydrogenase type 2 inhibitors for the treatment of osteoporosis.
J. Med. Chem. 56, 167-181 (2013)
Inhibition of 17β-HSD2 is an attractive mechanism for the treatment of osteoporosis. We report here the optimization of human 17β-HSD2 inhibitors in the 2,5-thiophene amide class by varying the size of the linker (n equals 0 and 2) between the amide moiety and the phenyl group. While none of the phenethylamides (n = 2) were active, most of the anilides (n = 0) turned out to moderately or strongly inhibit 17β-HSD2. The four most active compounds showed an IC(50) of around 60 nM and a very good selectivity toward 17β-HSD1, 17β-HSD4, 17β-HSD5, 11β-HSD1, 11β-HSD2 and the estrogen receptors α and β. The investigated compounds inhibited monkey 17β-HSD2 moderately, and one of them showed good inhibitory activity on mouse 17β-HSD2. SAR studies allowed a first characterization of the human 17β-HSD2 active site, which is predicted to be considerably larger than that of 17β-HSD1.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
4,5-disubstituted Cis-pyrrolidinones ; Estrogen-dependent Diseases ; Bicyclic Substituted Hydroxyphenylmethanones ; Hormone Replacement Therapy ; Human Placental Microsomes ; Nonsteroidal Inhibitors ; Biological Evaluation ; Ii 17-beta-hydroxysteroid-dehydrogenase ; 17-beta-hsd2 Inhibitors ; Dehydrogenase-activity
ISSN (print) / ISBN
0022-2623
e-ISSN
1520-4804
Journal
Journal of Medicinal Chemistry
Quellenangaben
Volume: 56,
Issue: 1,
Pages: 167-181
Publisher
American Chemical Society (ACS)
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Molekulare Endokrinologie und Metabolismus (MEM)