Structure-based discovery of novel amide-containing nicotinamide phosphoribosyltransferase (nampt) inhibitors

J Med Chem. 2013 Aug 22;56(16):6413-33. doi: 10.1021/jm4008664. Epub 2013 Jul 31.


Crystal structures of several urea- and thiourea-derived compounds in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein were utilized to design a potent amide-containing inhibitor bearing an aza-indole moiety (7, Nampt BC IC50 = 9.0 nM, A2780 cell proliferation IC50 = 10 nM). The Nampt-7 cocrystal structure was subsequently obtained and enabled the design of additional amide-containing inhibitors which incorporated various other fused 6,5-heterocyclic moieties and biaryl sulfone or sulfonamide motifs. Additional modifications of these molecules afforded many potent biaryl sulfone-containing Nampt inhibitors which also exhibited favorable in vitro ADME properties (microsomal and hepatocyte stability, MDCK permeability, plasma protein binding). An optimized compound (58) was a potent inhibitor of multiple cancer cell lines (IC50 <10 nM vs U251, HT1080, PC3, MiaPaCa2, and HCT116 lines), displayed acceptable mouse PK properties (F = 41%, CL = 52.4 mL/min/kg), and exhibited robust efficacy in a U251 mouse xenograft model.

MeSH terms

  • Animals
  • Drug Discovery*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Structure
  • Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors*
  • Spectrometry, Mass, Electrospray Ionization


  • Enzyme Inhibitors
  • Nicotinamide Phosphoribosyltransferase