Discovery of pyrrolidine-based β-secretase inhibitors: lead advancement through conformational design for maintenance of ligand binding efficiency

Bioorg Med Chem Lett. 2012 Jan 1;22(1):240-4. doi: 10.1016/j.bmcl.2011.11.024. Epub 2011 Nov 12.


We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold. Ultimately, the co-crystal structure was obtained revealing that these inhibitors interacted with the enzyme in a unique fashion. In all, the potency of the series was enhanced by 4 orders of magnitude from the HTS lead with concomitant increases in physical properties needed for series advancement. The progression of these developments in a systematic fashion is described.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / metabolism*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors
  • Chemistry, Pharmaceutical / methods*
  • Crystallization
  • Crystallography, X-Ray / methods
  • Drug Design
  • Enzyme Inhibitors / pharmacology
  • Inhibitory Concentration 50
  • Ligands
  • Models, Chemical
  • Protein Binding
  • Pyrrolidines / pharmacology*
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Ligands
  • Pyrrolidines
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human