The development of a structurally distinct series of BACE1 inhibitors via the (Z)-fluoro-olefin amide bioisosteric replacement

Bioorg Med Chem Lett. 2020 Jul 15;30(14):127240. doi: 10.1016/j.bmcl.2020.127240. Epub 2020 May 4.

Abstract

The (Z)-fluoro-olefin amide bioisosteric replacement is an effective tool for addressing various shortcomings of the parent amide. In an effort to fine tune ADME properties of BACE1 preclinical candidate AM-6494, a series of structurally distinct (Z)-fluoro-olefin containing analogs was developed that culminated in compound 15. Herein, we detail design considerations, synthetic challenges, structure activity relationship (SAR) studies, and in vivo properties of an advanced compound in this novel series of BACE1 inhibitors.

Keywords: (Z)-fluoro-olefin; BACE1; Bioisostere.

MeSH terms

  • Alkenes / chemical synthesis
  • Alkenes / chemistry
  • Alkenes / pharmacology*
  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Dose-Response Relationship, Drug
  • Drug Development*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Hydrocarbons, Fluorinated / chemical synthesis
  • Hydrocarbons, Fluorinated / chemistry
  • Hydrocarbons, Fluorinated / pharmacology*
  • Molecular Conformation
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Alkenes
  • Amides
  • Enzyme Inhibitors
  • Hydrocarbons, Fluorinated
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human