Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model

Bioorg Med Chem Lett. 2010 Nov 1;20(21):6231-6. doi: 10.1016/j.bmcl.2010.08.102. Epub 2010 Aug 24.

Abstract

In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Αβ by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30mpk BID for 2.5days.

MeSH terms

  • Alkylation
  • Alzheimer Disease
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Brain / metabolism
  • Cell Line
  • Dogs
  • Drug Design
  • Ethylamines / chemical synthesis*
  • Ethylamines / pharmacology*
  • Guinea Pigs
  • Humans
  • Indicators and Reagents
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology*
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Ethylamines
  • Indicators and Reagents
  • Protease Inhibitors
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human