Design and discovery of C2-fluoroalkyl iminothiazine dioxides as BACE inhibitors

Bioorg Med Chem Lett. 2022 Jan 15:56:128463. doi: 10.1016/j.bmcl.2021.128463. Epub 2021 Nov 24.

Abstract

This paper describes the structure-activity-relationships of novel fluoroalkyl substituents at the C2 position of iminothiazine dioxide beta secretase inhibitors. Key discoveries include reduced amidine basicity and its effect on Pgp, cell potency, and efficacy in various preclinical in vivo efficacy animal models. Findings from these structure-activity-relationships are discussed.

Keywords: Alzheimer's disease; BACE-1; Beta-secretase-1 inhibitor; CNS.

MeSH terms

  • Administration, Oral
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Molecular Structure
  • Oxides / administration & dosage
  • Oxides / chemistry
  • Oxides / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Thiazines / administration & dosage
  • Thiazines / chemistry
  • Thiazines / pharmacology*

Substances

  • Enzyme Inhibitors
  • Oxides
  • Thiazines
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human