Addressing cytotoxicity of 1,4-biphenyl amide derivatives: Discovery of new potent and selective 17β-hydroxysteroid dehydrogenase type 2 inhibitors

Emanuele Marco Gargano; Enrico Perspicace; Angelo Carotti; Sandrine Marchais-Oberwinkler; Rolf W Hartmann

doi:10.1016/j.bmcl.2015.11.047

Addressing cytotoxicity of 1,4-biphenyl amide derivatives: Discovery of new potent and selective 17β-hydroxysteroid dehydrogenase type 2 inhibitors

Bioorg Med Chem Lett. 2016 Jan 1;26(1):21-4. doi: 10.1016/j.bmcl.2015.11.047. Epub 2015 Nov 23.

Authors

Emanuele Marco Gargano¹, Enrico Perspicace¹, Angelo Carotti², Sandrine Marchais-Oberwinkler³, Rolf W Hartmann³

Affiliations

¹ Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany.
² Dipartimento di Farmacia Scienze del Farmaco, Università degli Studi di Bari, V. Orabona 4, I-70125 Bari, Italy.
³ Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus E8.1, D-66123 Saarbrücken, Germany.

PMID: 26615885
DOI: 10.1016/j.bmcl.2015.11.047

Abstract

Four different classes of new 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) inhibitors were synthesized, in order to lower the cytotoxicity exhibited by the lead compound A, via disrupting the linearity and the aromaticity of the biphenyl moiety. Compounds 3, 4, 7a and 8 displayed comparable or better inhibitory activity and selectivity, as well as a lower cytotoxic effect, compared to the reference compound A. The best compound 4 (IC50=160nM, selectivity factor=168, LD50≈25μM) turned out as new lead compound for inhibition of 17β-HSD2.

Keywords: 17β-HSD1; 17β-HSD2; Biphenyl; Cytotoxicity; Osteoporosis.

Publication types

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

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Biphenyl Compounds / chemical synthesis
Biphenyl Compounds / chemistry
Biphenyl Compounds / pharmacology*
Cell Survival / drug effects
Cytotoxins / chemical synthesis
Cytotoxins / chemistry
Cytotoxins / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Estradiol Dehydrogenases / antagonists & inhibitors*
Estradiol Dehydrogenases / metabolism
HEK293 Cells
Humans
Molecular Structure
Structure-Activity Relationship

Substances

Amides
Biphenyl Compounds
Cytotoxins
Enzyme Inhibitors
Estradiol Dehydrogenases
HSD17B2 protein, human