A novel class of oral direct renin inhibitors: highly potent 3,5-disubstituted piperidines bearing a tricyclic p3-p1 pharmacophore

J Med Chem. 2013 Mar 28;56(6):2196-206. doi: 10.1021/jm301706j. Epub 2013 Mar 15.


A small library of fragments comprising putative recognition motifs for the catalytic dyad of aspartic proteases was generated by in silico similarity searches within the corporate compound deck based on rh-renin active site docking and scoring filters. Subsequent screening by NMR identified the low-affinity hits 3 and 4 as competitive active site binders, which could be shown by X-ray crystallography to bind to the hydrophobic S3-S1 pocket of rh-renin. As part of a parallel multiple hit-finding approach, the 3,5-disubstituted piperidine (rac)-5 was discovered by HTS using a enzymatic assay. X-ray crystallography demonstrated the eutomer (3S,5R)-5 to be a peptidomimetic inhibitor binding to a nonsubstrate topography of the rh-renin prime site. The design of the potent and selective (3S,5R)-12 bearing a P3(sp)-tethered tricyclic P3-P1 pharmacophore derived from 3 is described. (3S,5R)-12 showed oral bioavailability in rats and demonstrated blood pressure lowering activity in the double-transgenic rat model.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Drug Design*
  • Inhibitory Concentration 50
  • Models, Molecular
  • Piperidines / administration & dosage
  • Piperidines / chemistry*
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology*
  • Protease Inhibitors / administration & dosage
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology*
  • Protein Conformation
  • Rats
  • Renin / antagonists & inhibitors*
  • Renin / chemistry


  • Piperidines
  • Protease Inhibitors
  • Renin