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Eur J Med Chem. 2014 Nov 24;87:203-19. doi: 10.1016/j.ejmech.2014.09.061. Epub 2014 Sep 20.

Metabolic stability optimization and metabolite identification of 2,5-thiophene amide 17β-hydroxysteroid dehydrogenase type 2 inhibitors.

Author information

1
Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany.
2
ElexoPharm GmbH, Campus A1(2), D-66123 Saarbrücken, Germany.
3
Dipartimento Farmaco-Chimico, Università degli Studi di Bari, V. Orabona 4, I-70125 Bari, Italy.
4
Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany. Electronic address: s.marchais@mx.uni-saarland.de.
5
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.

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.

KEYWORDS:

17β-HSD2; Inhibitor design; Metabolic stability; Metabolite identification; Osteoporosis; cLogP

PMID:
25259513
DOI:
10.1016/j.ejmech.2014.09.061
[Indexed for MEDLINE]

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