Carbazole-containing arylcarboxamides as BACE1 inhibitors

Bioorg Med Chem Lett. 2011 Nov 15;21(22):6657-61. doi: 10.1016/j.bmcl.2011.09.064. Epub 2011 Sep 21.

Abstract

β-Secretase (BACE1) is widely recognized as a prime drug target for the treatment of Alzheimer's disease (AD). In this Letter, we report the synthesis and the BACE1 inhibitory activity of novel, variously substituted N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-arylcarboxamides. The best results have been obtained with the introduction of a 4-OMe substituent (IC(50)=3.8 μM) or a 3,4-dichloro substituent (IC(50)=2.5 μM) in the amidic aromatic ring. The blood-brain barrier penetration predictions resulted to be promising for this type of compounds. To better understand the structure-activity relationships (SAR) of the new derivatives, a docking study procedure has been applied exploiting different conformational and ionic states of BACE1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy
  • Amides / chemistry*
  • Amides / pharmacokinetics
  • Amides / pharmacology*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Blood-Brain Barrier / metabolism
  • Carbazoles / chemistry*
  • Carbazoles / pharmacokinetics
  • Carbazoles / pharmacology*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Amides
  • Carbazoles
  • Enzyme Inhibitors
  • carbazole
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human