title: Metabolic stability optimization and metabolite identification of 2,5-thiophene amide 17β-hydroxysteroid dehydrogenase type 2 inhibitors.
abstract: 17β-HSD2 is a promising new target for the treatment of osteoporosis. In this paper, a rational strategy to overcome the metabolic liability in the 2,5-thiophene amide class of 17β-HSD2 inhibitors is described, and the biological activity of the new inhibitors. Applying different strategies, as lowering the cLogP or modifying the structures of the molecules, compounds 27, 31 and 35 with strongly improved metabolic stability were obtained. For understanding biotransformation in the 2,5-thiophene amide class the main metabolic pathways of three properly selected compounds were elucidated.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany.
authors.forename: Emanuele M
authors.initials: EM
authors.lastname: Gargano
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany.
authors.forename: Enrico
authors.initials: E
authors.lastname: Perspicace
authors.affiliation: ElexoPharm GmbH, Campus A1(2), D-66123 Saarbrücken, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Hanke
authors.affiliation: Dipartimento Farmaco-Chimico, Università degli Studi di Bari, V. Orabona 4, I-70125 Bari, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany. Electronic address: s.marchais@mx.uni-saarland.de.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchais-Oberwinkler
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2(3), D-66123 Saarbrücken, Germany. Electronic address: rwh@mx.uni-saarland.de.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry*
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D013876:Thiophenes; D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human
keywords: 17β-HSD2; Inhibitor design; Metabolic stability; Metabolite identification; Osteoporosis; cLogP