Discovery of benzodihydroisofurans as novel, potent, bioavailable and brain-penetrant prolylcarboxypeptidase inhibitors

Bioorg Med Chem Lett. 2012 Feb 15;22(4):1550-6. doi: 10.1016/j.bmcl.2012.01.002. Epub 2012 Jan 10.

Abstract

A series of benzodihydroisofurans were discovered as novel, potent, bioavailable and brain-penetrant prolylcarboxypeptidase (PrCP) inhibitors. The structure-activity relationship (SAR) is focused on improving PrCP activity and metabolic stability, and reducing plasma protein binding. In the established diet-induced obese (eDIO) mouse model, compound ent-3a displayed target engagement both in plasma and in brain. However, this compound failed to induce significant body weight loss in eDIO mice in a five-day study.

MeSH terms

  • Animals
  • Carboxypeptidases / antagonists & inhibitors*
  • Cells, Cultured
  • Disease Models, Animal
  • Drug Discovery*
  • Drug Stability
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Furans / chemical synthesis
  • Furans / chemistry*
  • Furans / pharmacology*
  • Humans
  • Mice
  • Mice, Obese
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Furans
  • Carboxypeptidases
  • lysosomal Pro-X carboxypeptidase