Renin inhibitors containing C-termini derived from mercaptoheterocycles

J Med Chem. 1992 May 29;35(11):2103-12. doi: 10.1021/jm00089a023.


A series of transition-state analogues having heterocyclythio C-termini has been synthesized and evaluated for inhibition of human renin. Addition of mercaptoheterocycles to a chiral Boc-amino epoxide intermediate led, after several steps, to the target [(2R,3S)-3-(BocPheHis-amino)-4-cyclohexyl-2-hydroxy-1-butyl]thio derivatives. Oxidation of the thioether to sulfone was also investigated. Several of the compounds, especially those derived from N1-substituted-5-mercaptotetrazoles or N4-substituted-3-mercapto-5-(trifluoromethyl)-1,2,4-triazoles, were moderately potent inhibitors of human plasma renin, having IC50 values of 30-40 nM. When selected compounds were administered intravenously to sodium-deficient rhesus monkeys at 0.3-1.2 mg/kg, they reduced plasma renin activity by 75-98%. However, this inhibition and the accompanying drop in blood pressure were of short duration.

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Female
  • Heart Rate / drug effects
  • Humans
  • Macaca mulatta
  • Male
  • Molecular Structure
  • Renin / antagonists & inhibitors*
  • Renin / blood
  • Sodium / deficiency
  • Sulfhydryl Compounds / chemical synthesis*
  • Sulfhydryl Compounds / pharmacology
  • Tetrazoles / chemical synthesis*
  • Tetrazoles / pharmacology
  • Triazoles / chemical synthesis*
  • Triazoles / pharmacology


  • Sulfhydryl Compounds
  • Tetrazoles
  • Triazoles
  • Sodium
  • Renin