Macrocyclic prolinyl acyl guanidines as inhibitors of β-secretase (BACE)

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5040-7. doi: 10.1016/j.bmcl.2015.10.031. Epub 2015 Oct 20.

Abstract

The synthesis, evaluation, and structure-activity relationships of a class of acyl guanidines which inhibit the BACE-1 enzyme are presented. The prolinyl acyl guanidine chemotype (7c), unlike compounds of the parent isothiazole chemotype (1), yielded compounds with good agreement between their enzymatic and cellular potency as well as a reduced susceptibility to P-gp efflux. Further improvements in potency and P-gp ratio were realized via a macrocyclization strategy. The in vivo profile in wild-type mice and P-gp effects for the macrocyclic analog 21c is presented.

Keywords: Alzheimer’s disease; BACE.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid beta-Peptides / biosynthesis
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Caco-2 Cells
  • Cathepsin D / antagonists & inhibitors
  • Cathepsin E / antagonists & inhibitors
  • Dogs
  • Guanidines / chemical synthesis
  • Guanidines / pharmacology*
  • Humans
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / pharmacology*
  • Madin Darby Canine Kidney Cells
  • Male
  • Mice
  • Molecular Docking Simulation
  • Pepsin A / antagonists & inhibitors
  • Proline / analogs & derivatives*
  • Proline / chemical synthesis
  • Proline / pharmacology*
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / pharmacology*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Amyloid beta-Peptides
  • Guanidines
  • Macrocyclic Compounds
  • Protease Inhibitors
  • Proline
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Pepsin A
  • Cathepsin E
  • Bace1 protein, mouse
  • Cathepsin D