title: Addressing cytotoxicity of 1,4-biphenyl amide derivatives: Discovery of new potent and selective 17β-hydroxysteroid dehydrogenase type 2 inhibitors.
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.
authors.affiliation: Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany.
authors.forename: Emanuele Marco
authors.initials: EM
authors.lastname: Gargano
authors.affiliation: Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany.
authors.forename: Enrico
authors.initials: E
authors.lastname: Perspicace
authors.affiliation: Dipartimento di Farmacia Scienze del Farmaco, Università degli Studi di Bari, V. Orabona 4, I-70125 Bari, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
authors.affiliation: 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.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchais-Oberwinkler
authors.affiliation: 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.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001713:Biphenyl Compounds; D003603:Cytotoxins; D004791:Enzyme Inhibitors; D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human
keywords: 17β-HSD1; 17β-HSD2; Biphenyl; Cytotoxicity; Osteoporosis