Renin inhibitors containing new P1-P1' dipeptide mimetics with heterocycles in P1'

J Med Chem. 1992 Sep 18;35(19):3525-36. doi: 10.1021/jm00097a010.


A series of renin inhibitors containing new P1-P1' dipeptide mimetics are presented. The P1-P1' mimetics were obtained from (4S,5S)-3-(tert-butoxycarbonyl)-4-(cyclohexylmethyl)-5-[(omega- mesyloxy)alkyl]-2,2-dimethyloxazolidines 5b, 9, and 11b by nucleophilic substitution of the mesylate groups with the sodium salts of mercapto- and hydroxyheterocycles. Removal of the protecting groups and stepwise acylations with amino acid derivatives provided renin inhibitors with a length of a tripeptide. Replacement of P2 histidine by other amino acids maintained or enhanced renin inhibitory potency. By alteration of P3 phenylalanine, compounds with IC50 values in the nanomolar range and stability against chymotrypsin were obtained. Finally, the effect of the C-terminal heterocycle on the renin inhibition was studied. Compound XVII was examined in vivo for its hypotensive effects. In salt-depleted cynomolgus monkeys, XVII inhibited plasma renin activity and lowered blood pressure after oral administration of a dose of 10 mg/kg.

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Chromatography, High Pressure Liquid
  • Dipeptides / chemical synthesis*
  • Dipeptides / chemistry
  • Dipeptides / pharmacology
  • Female
  • Heart Rate / drug effects
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Macaca fascicularis
  • Models, Molecular
  • Renin / antagonists & inhibitors*
  • Renin / blood
  • Structure-Activity Relationship


  • Dipeptides
  • Heterocyclic Compounds
  • Renin