Design, synthesis, and X-ray structural studies of BACE-1 inhibitors containing substituted 2-oxopiperazines as P1'-P2' ligands

Bioorg Med Chem Lett. 2017 Jun 1;27(11):2432-2438. doi: 10.1016/j.bmcl.2017.04.011. Epub 2017 Apr 8.

Abstract

We report the design and synthesis of a series of BACE1 inhibitors incorporating mono- and bicyclic 6-substituted 2-oxopiperazines as novel P1' and P2' ligands and isophthalamide derivative as P2-P3 ligands. Among mono-substituted 2-oxopiperazines, inhibitor 5a with N-benzyl-2-oxopiperazine and isophthalamide showed potent BACE1 inhibitory activity (Ki=2nM). Inhibitor 5g, with N-benzyl-2-oxopiperazine and substituted indole-derived P2-ligand showed a reduction in potency. The X-ray crystal structure of 5g-bound BACE1 was determined and used to design a set of disubstituted 2-oxopiperazines and bicyclic derivatives that were subsequently investigated. Inhibitor 6j with an oxazolidinone derivative showed a BACE1 inhibitory activity of 23nM and cellular EC50 of 80nM.

Keywords: Alzheimer’s disease; BACE-1; Memapsin 2; Protease inhibitors; β-Secretase.

Publication types

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

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Phthalic Acids / chemical synthesis
  • Phthalic Acids / chemistry*
  • Piperazines / chemical synthesis
  • Piperazines / chemistry*
  • Structure-Activity Relationship

Substances

  • Phthalic Acids
  • Piperazines
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases