3,3-Difluoro-3,4,5,6-tetrahydropyridin-2-amines: Potent and permeable BACE-1 inhibitors

Bioorg Med Chem Lett. 2020 Apr 15;30(8):126999. doi: 10.1016/j.bmcl.2020.126999. Epub 2020 Jan 27.

Abstract

Since its discovery in 1999, BACE-1, a membrane anchored aspartyl protease expressed primarily in the CNS, has been the target of numerous medicinal chemistry research programs. These efforts have produced highly potent inhibitors with nanomolar affinity and ever-increasing structural complexity. However, only a handful of these molecules have been able to combine in vitro potency with CNS permeability and progressed to the clinic. Herein, we describe a set of novel piperidine-based inhibitors. This investigation culminated with the identification of 43, a highly potent (IC50: 1.5 nM), permeable BACE-1 inhibitor with a low susceptibility to Pgp-mediatedefflux.

Keywords: Alzheimer’s disease; Amidine; BACE inhibitor; pKa; β-Secretase.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Protease Inhibitors
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human