Design of pentapeptidic BACE1 inhibitors with carboxylic acid bioisosteres at P1' and P4 positions

Bioorg Med Chem. 2010 May 1;18(9):3175-86. doi: 10.1016/j.bmc.2010.03.032. Epub 2010 Mar 21.

Abstract

We previously reported potent BACE1 inhibitors KMI-420 and KMI-570 possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. Acidic moieties at the P(1)(') and P(4) positions of KMI inhibitors are thought to be unfavorable in terms of membrane permeability across the blood-brain barrier. Herein, we replaced acidic moieties at the P(4) position with hydrogen bond accepting groups and acidic moieties at the P(1)(') position with less acidic and similar molecular-size moieties (carboxylic acid or tetrazole bioisosteres). These inhibitors exhibited improved BACE1 inhibitory activities and a thorough quantitative structure-activity relationship study was performed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Carboxylic Acids / chemistry
  • Crystallography, X-Ray
  • Drug Design*
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Humans
  • Hydrogen Bonding
  • Hydrogen-Ion Concentration
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Thiazoles / chemistry
  • Triazoles / chemistry

Substances

  • Carboxylic Acids
  • Enzyme Inhibitors
  • KMI-420
  • KMI-570
  • Oligopeptides
  • Thiazoles
  • Triazoles
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human