Synthesis and profiling of a diverse collection of azetidine-based scaffolds for the development of CNS-focused lead-like libraries

J Org Chem. 2012 Sep 7;77(17):7187-211. doi: 10.1021/jo300974j. Epub 2012 Aug 10.


The synthesis and diversification of a densely functionalized azetidine ring system to gain access to a wide variety of fused, bridged, and spirocyclic ring systems is described. The in vitro physicochemical and pharmacokinetic properties of representative library members are measured in order to evaluate the use of these scaffolds for the generation of lead-like molecules to be used in targeting the central nervous system. The solid-phase synthesis of a 1976-membered library of spirocyclic azetidines is also described.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azetidines / blood
  • Azetidines / chemical synthesis
  • Azetidines / pharmacokinetics*
  • Caco-2 Cells
  • Cell Membrane Permeability / drug effects
  • Central Nervous System / cytology
  • Central Nervous System / drug effects*
  • Endothelial Cells / drug effects
  • Humans
  • Mice
  • Molecular Structure
  • Small Molecule Libraries / chemical synthesis*
  • Small Molecule Libraries / pharmacokinetics*
  • Solubility
  • Spiro Compounds / blood
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / pharmacokinetics*
  • Stereoisomerism


  • Azetidines
  • Small Molecule Libraries
  • Spiro Compounds
  • azetidine