Synthesis and in vivo evaluation of cyclic diaminopropane BACE-1 inhibitors

Bioorg Med Chem Lett. 2011 Nov 15;21(22):6909-15. doi: 10.1016/j.bmcl.2011.06.116. Epub 2011 Jul 2.

Abstract

The synthesis, evaluation, and structure-activity relationships of a set of related constrained diaminopropane inhibitors of BACE-1 are described. The full in vivo profile of an optimized inhibitor in both normal and P-gp deficient mice is compared with data generated in normal rats.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Alzheimer Disease / drug therapy
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors
  • Aspartic Acid Endopeptidases / metabolism
  • Crystallography, X-Ray
  • Diamines / chemical synthesis
  • Diamines / chemistry*
  • Diamines / pharmacokinetics
  • Diamines / pharmacology*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Knockout
  • Models, Molecular
  • Rats
  • Structure-Activity Relationship

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Diamines
  • Enzyme Inhibitors
  • 1,2-diaminopropane
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human