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.
Emanuele Marco Gargano  1 ,  Enrico Perspicace  1 ,  Angelo Carotti  2 ,  Sandrine Marchais-Oberwinkler  3 ,  Rolf W Hartmann  3
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.
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