Discovery of a series of efficient, centrally efficacious BACE1 inhibitors through structure-based drug design

J Med Chem. 2015 Mar 26;58(6):2678-702. doi: 10.1021/jm501833t. Epub 2015 Mar 9.

Abstract

The identification of centrally efficacious β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired absorption, distribution, metabolism, and excretion (ADME) properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related cathepsin D or negatively impacting brain penetration and ADME alignment, as exemplified by 36. Upon oral administration, these inhibitors exhibit robust brain availability and are efficacious in lowering central Amyloid β (Aβ) levels in mouse and dog. In addition, chronic treatment in aged PS1/APP mice effects a decrease in the number and size of Aβ-derived plaques. Most importantly, evaluation of 36 in a 2-week exploratory toxicology study revealed no accumulation of autofluorescent material in retinal pigment epithelium or histology findings in the eye, issues observed with earlier BACE1 inhibitors.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alzheimer Disease / drug therapy
  • Amidines / chemistry*
  • Amidines / pharmacokinetics
  • Amidines / pharmacology
  • Amidines / therapeutic use*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / pathology
  • Dogs
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Male
  • Mice
  • Models, Molecular
  • Plaque, Amyloid / drug therapy*
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • Rats
  • Rats, Wistar
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / pharmacokinetics
  • Sulfhydryl Compounds / pharmacology
  • Sulfhydryl Compounds / therapeutic use

Substances

  • Amidines
  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • Sulfhydryl Compounds
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human

Associated data

  • PDB/4WY1
  • PDB/4WY6
  • PDB/4X2L