Rational design and asymmetric synthesis of potent and neurotrophic ligands for FK506-binding proteins (FKBPs)

Angew Chem Int Ed Engl. 2015 Jan 2;54(1):345-8. doi: 10.1002/anie.201408776. Epub 2014 Nov 20.


To create highly efficient inhibitors for FK506-binding proteins, a new asymmetric synthesis for pro-(S)-C(5) -branched [4.3.1] aza-amide bicycles was developed. The key step of the synthesis is an HF-driven N-acyliminium cyclization. Functionalization of the C(5) moiety resulted in novel protein contacts with the psychiatric risk factor FKBP51, which led to a more than 280-fold enhancement in affinity. The most potent ligands facilitated the differentiation of N2a neuroblastoma cells with low nanomolar potency.

Keywords: FKBP ligands; cyclization; drug discovery; neurotrophic agents; rational design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azabicyclo Compounds / chemistry*
  • Azabicyclo Compounds / pharmacology
  • Drug Design*
  • Humans
  • Ligands
  • Molecular Docking Simulation
  • Protein Binding
  • Tacrolimus Binding Proteins / antagonists & inhibitors
  • Tacrolimus Binding Proteins / chemistry
  • Tacrolimus Binding Proteins / metabolism*


  • Azabicyclo Compounds
  • Ligands
  • Tacrolimus Binding Proteins