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

Medicinal Chemistry


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.


Stachel, Shawn J; Steele, Thomas G; Petrocchi, Alessia; Haugabook, Sharie; McGaughey, Georgia; Katharine Holloway, M; Allison, Timothy; Munshi, Sanjeev; Zuck, Paul; Colussi, Dennis; Tugasheva, Katherine; Wolfe, Abigail; Graham, Samuel L; Vacca, Joseph P;


  • 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

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