1,3-Oxazines as BACE1 and/or BACE2 inhibitors: a patent evaluation (WO2012156284)

Expert Opin Ther Pat. 2013 Aug;23(8):1069-73. doi: 10.1517/13543776.2013.818134. Epub 2013 Jul 10.

Abstract

This patent review covers the contents of Hoffman-La Roche and Siena Biotech's patent application WO2012156284 titled '1,3-Oxazines as BACE1 and/or BACE2 Inhibitors.' Beta-site amyloid precursor protein-converting enzyme (BACE1) and BACE2 activities are reported to support the claimed compounds' use as therapeutics for Alzheimer's disease and type II diabetes, respectively. A common core motif of the claimed compounds is the six-membered 1,3-oxazine system. To gain access to the S3 and S3 subpocket of the BACE1 active site, various linkers are described including nitrogen- and oxygen-based, aryl, and amide-based linkers. Of the 65 compounds claimed, 6 had IC50s less than 100 nM in the BACE1 cell assay. Cellular BACE2 inhibition data are reported for 20 compounds with 2 under 100 nM.

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / physiopathology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / physiopathology
  • Drug Design
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology
  • Inhibitory Concentration 50
  • Oxazines / administration & dosage
  • Oxazines / chemistry
  • Oxazines / pharmacology*
  • Patents as Topic

Substances

  • Hypoglycemic Agents
  • Oxazines
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE2 protein, human
  • BACE1 protein, human