Synthesis, SAR, and X-ray structure of human BACE-1 inhibitors with cyclic urea derivatives

Bioorg Med Chem Lett. 2008 May 1;18(9):2900-4. doi: 10.1016/j.bmcl.2008.03.081. Epub 2008 Apr 8.

Abstract

We describe synthesis and evaluation of a series of cyclic urea derivatives with hydroxylethylamine isostere. Modification of P3, P1, and P2' and combination of SAR display a >100-fold increase in potency with good cellular activity (IC(50)=0.15microM) relative to the previously reported compound 3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Cell Line
  • Crystallography, X-Ray
  • Cyclization
  • Ethylamines / chemical synthesis
  • Ethylamines / pharmacology*
  • Humans
  • Hydroxylation
  • Inhibitory Concentration 50
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Urea / analogs & derivatives
  • Urea / chemical synthesis
  • Urea / pharmacology*

Substances

  • Ethylamines
  • Protease Inhibitors
  • Urea
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human

Associated data

  • PDB/3CKP
  • PDB/3CKR