Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind beta-secretase in a N-terminal 10s-loop down conformation

Bioorg Med Chem Lett. 2007 Mar 15;17(6):1788-92. doi: 10.1016/j.bmcl.2006.12.051. Epub 2006 Dec 21.

Abstract

A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-1 inhibitors containing an amine transition-state isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a trans-S,S-methyl cyclopropane P(3) which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Baculoviridae / drug effects
  • Baculoviridae / enzymology
  • Biological Availability
  • Cells, Cultured
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation
  • Molecular Weight
  • Niacinamide / chemical synthesis*
  • Niacinamide / pharmacokinetics
  • Niacinamide / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Niacinamide
  • isonicotinamide
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human