Phe*-Ala-based pentapeptide mimetics are BACE inhibitors: P2 and P3 SAR

Bioorg Med Chem Lett. 2004 Jan 5;14(1):239-43. doi: 10.1016/j.bmcl.2003.09.084.

Abstract

We describe herein the syntheses and evaluation of a series of C-termini pyridyl containing Phe*-Ala-based BACE inhibitors (5-19). In conjunction with four fixed residues at the P1 (Phe), P1' (Ala), P2' (Val), and P2' cap (Pyr.), rather detailed SAR modifications at P2 and P3 positions were pursued. The promising inhibitors emerging from this SAR investigation, 12 and 17 demonstrated very good enzyme potency (IC(50)=45 nM) and cellular activity (IC(50)=0.4 microM).

MeSH terms

  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Cell Line
  • Dipeptides / chemical synthesis*
  • Dipeptides / toxicity
  • Endopeptidases / metabolism*
  • Humans
  • Molecular Mimicry
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / toxicity
  • Structure-Activity Relationship

Substances

  • Dipeptides
  • Protease Inhibitors
  • phenylalanylalanine
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human