17β-Hydroxysteroid Dehydrogenase Type 2 Inhibition: Discovery of Selective and Metabolically Stable Compounds Inhibiting Both the Human Enzyme and Its Murine Ortholog

Emanuele M Gargano; Giuseppe Allegretta; Enrico Perspicace; Angelo Carotti; Chris Van Koppen; Martin Frotscher; Sandrine Marchais-Oberwinkler; Rolf W Hartmann

doi:10.1371/journal.pone.0134754

17β-Hydroxysteroid Dehydrogenase Type 2 Inhibition: Discovery of Selective and Metabolically Stable Compounds Inhibiting Both the Human Enzyme and Its Murine Ortholog

PLoS One. 2015 Jul 31;10(7):e0134754. doi: 10.1371/journal.pone.0134754. eCollection 2015.

Authors

Emanuele M Gargano¹, Giuseppe Allegretta², Enrico Perspicace¹, Angelo Carotti³, Chris Van Koppen⁴, Martin Frotscher¹, Sandrine Marchais-Oberwinkler⁵, Rolf W Hartmann⁵

Affiliations

¹ Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
² Helmholtz Institute for Pharmaceutical Research Saarland, Saarbrücken, Germany.
³ Dipartimento Farmaco-Chimico, Università degli Studi di Bari, Bari, Italy.
⁴ ElexoPharm GmbH, Saarbrücken, Germany.
⁵ Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland, Saarbrücken, Germany.

Abstract

Design and synthesis of a new class of inhibitors for the treatment of osteoporosis and its comparative h17β-HSD2 and m17β-HSD2 SAR study are described. 17a is the first compound to show strong inhibition of both h17β-HSD2 and m17β-HSD2, intracellular activity, metabolic stability, selectivity toward h17β-HSD1, m17β-HSD1 and estrogen receptors α and β as well as appropriate physicochemical properties for oral bioavailability. These properties make it eligible for pre-clinical animal studies, prior to human studies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Estradiol Dehydrogenases / antagonists & inhibitors*
Humans
Mice
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Estradiol Dehydrogenases
HSD17B2 protein, human

Grants and funding

The authors acknowledge the Deutsche Forschungsgemeinschaft (DFG) for financial support (Grants HA1315/12-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Elexopharm GmbH had no financial interest in this collaboration.