Design and preparation of potent, nonpeptidic, bioavailable renin inhibitors

J Med Chem. 2009 Jun 25;52(12):3689-702. doi: 10.1021/jm900022f.


Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.

MeSH terms

  • Azabicyclo Compounds / chemical synthesis*
  • Azabicyclo Compounds / pharmacology*
  • Binding Sites
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Molecular Conformation
  • Renin / antagonists & inhibitors*
  • Structure-Activity Relationship


  • Azabicyclo Compounds
  • Enzyme Inhibitors
  • Renin

Associated data

  • PDB/3G62
  • PDB/3G70
  • PDB/3G72