Discovery of furo[2,3-d][1,3]thiazinamines as beta amyloid cleaving enzyme-1 (BACE1) inhibitors

Bioorg Med Chem Lett. 2016 Dec 1;26(23):5729-5731. doi: 10.1016/j.bmcl.2016.10.055. Epub 2016 Oct 20.

Abstract

This Letter describes the synthesis and structure-activity relationships of a series of furo[2,3-d][1,3]thiazinamine BACE1 inhibitors. The co-crystal structure of a representative thiazinamine 2e bound with the BACE1 active site displayed a binding mode driven by interactions with the catalytic aspartate dyad and engagement of the biaryl amide toward the S1 and S3 pockets. This work indicates that furo[2,3-d]thiazine can serve as a viable bioisostere of the known furo[3,4-d]thiazine.

Keywords: Alzheimer’s disease; BACE1 inhibitor; Furo[2,3-d][1,3]thiazinamine.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / chemistry
  • Amyloid Precursor Protein Secretases / metabolism
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / chemistry
  • Aspartic Acid Endopeptidases / metabolism
  • Catalytic Domain
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Furans / chemistry*
  • Furans / pharmacology*
  • Humans
  • Models, Molecular
  • Protein Binding
  • Thiazines / chemistry*
  • Thiazines / pharmacology*

Substances

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