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Structural Optimization of 2,5-Thiophene Amides as Highly Potent and Selective 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibitors for the Treatment of Osteoporosis

Marchais-Oberwinkler, Sandrine and Xu, Kuiying and Wetzel, Marie and Perspicace, Enrico and Negri, Matthias and Meyer, Arne and Odermatt, Alex and Möller, Gabriele and Adamski, Jerzy and Hartmann, Rolf W.. (2013) Structural Optimization of 2,5-Thiophene Amides as Highly Potent and Selective 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibitors for the Treatment of Osteoporosis. Journal of Medicinal Chemistry, Vol. 56, H. 1. S. 167-181.

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Official URL: http://edoc.unibas.ch/dok/A6083227

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Abstract

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.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)
UniBasel Contributors:Odermatt, Alex and Meyer, Arne
Item Type:Article, refereed
Bibsysno:Link to catalogue
Publisher:American Chemical Society
ISSN:0022-2623
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:24 May 2013 09:22
Deposited On:24 May 2013 09:05

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