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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry
  • Amides / pharmacology*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Estradiol Dehydrogenases / antagonists & inhibitors*
  • Estradiol Dehydrogenases / metabolism*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Thiophenes / chemistry*

Substances

  • Amides
  • Enzyme Inhibitors
  • Thiophenes
  • Estradiol Dehydrogenases
  • HSD17B2 protein, human