Design, synthesis and evaluation of 2-amino-imidazol-4-one derivatives as potent β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) inhibitors

Bioorg Med Chem Lett. 2019 Dec 15;29(24):126772. doi: 10.1016/j.bmcl.2019.126772. Epub 2019 Oct 28.

Abstract

Inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) to prevent brain β-amyloid (Aβ) peptide's formation is a potential effective approach to treat Alzheimer's disease. In this report we described a structure-based optimization of a series of BACE1 inhibitors derived from an iminopyrimidinone scaffold W-41 (IC50 = 7.1 μM) by Wyeth, which had good selectivity and brain permeability but low activity. The results showed that occupying the S3 cavity of BACE1 enzyme could be an effective strategy to increase the biological activity, and five compounds exhibited stronger inhibitory activity and higher liposolubility than W-41, with L-5 was the most potent inhibitor against BACE1 (IC50 = 0.12 μM, logP = 2.49).

Keywords: Alzheimer’s disease; BACE1 inhibitors; Design and synthesis; Iminopyrimidinone scaffold; Structure–activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid beta-Protein Precursor / metabolism*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Humans
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Protein Precursor
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human