Monosubstituted γ-lactam and conformationally constrained 1,3-diaminopropan-2-ol transition-state isostere inhibitors of β-secretase (BACE)

Bioorg Med Chem Lett. 2011 Nov 15;21(22):6916-24. doi: 10.1016/j.bmcl.2011.06.109. Epub 2011 Jun 30.

Abstract

The synthesis, evaluation, and structure-activity relationships of a class of γ-lactam 1,3-diaminopropan-2-ol transition-state isostere inhibitors of BACE are discussed. Two strategies for optimizing lead compound 1a are presented. Reducing the overall size of the inhibitors resulted in the identification of γ-lactam 1i, whereas the introduction of conformational constraint on the prime-side of the inhibitor generated compounds such as the 3-hydroxypyrrolidine inhibitor 28n. The full in vivo profile of 1i in rats and 28n in Tg 2576 mice is presented.

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / enzymology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Lactams / chemical synthesis
  • Lactams / chemistry*
  • Lactams / pharmacokinetics
  • Lactams / pharmacology*
  • Mice
  • Models, Molecular
  • Rats
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Lactams
  • Amyloid Precursor Protein Secretases