Macrocyclic BACE-1 inhibitors acutely reduce Abeta in brain after po application

Bioorg Med Chem Lett. 2010 Jan 15;20(2):603-7. doi: 10.1016/j.bmcl.2009.11.092. Epub 2009 Nov 22.

Abstract

A series of macrocyclic peptidic BACE-1 inhibitors was designed. While potency on BACE-1 was rather high, the first set of compounds showed poor brain permeation and high efflux in the MDRI-MDCK assay. The replacement of the secondary benzylamino group with a phenylcyclopropylamino group maintained potency on BACE-1, while P-glycoprotein-mediated efflux was significantly reduced and brain permeation improved. Several compounds from this series demonstrated acute reduction of Abeta in human APP-wildtype transgenic (APP51/16) mice after oral administration.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Benzamides / chemical synthesis
  • Benzamides / chemistry*
  • Benzamides / pharmacology
  • Binding Sites
  • Brain / metabolism*
  • Cell Line
  • Crystallography, X-Ray
  • Humans
  • Lactams / chemical synthesis
  • Lactams / chemistry*
  • Lactams / pharmacology
  • Macrocyclic Compounds / chemistry*
  • Macrocyclic Compounds / pharmacology
  • Mice
  • Mice, Transgenic
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Amyloid beta-Peptides
  • Benzamides
  • Lactams
  • Macrocyclic Compounds
  • NB 216
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse