title: 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibition: Discovery of Selective and Metabolically Stable Compounds Inhibiting Both the Human Enzyme and Its Murine Ortholog.
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.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
authors.forename: Emanuele M
authors.initials: EM
authors.lastname: Gargano
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland, Saarbrücken, Germany.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Allegretta
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
authors.forename: Enrico
authors.initials: E
authors.lastname: Perspicace
authors.affiliation: Dipartimento Farmaco-Chimico, Università degli Studi di Bari, Bari, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
authors.affiliation: ElexoPharm GmbH, Saarbrücken, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Van Koppen
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Frotscher
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland, Saarbrücken, Germany.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchais-Oberwinkler
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland, Saarbrücken, Germany.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human