Renin inhibitors containing C-termini derived from mercaptoheterocycles

Authors:
  • CCChristine L. Cantone
    Christine L. Cantone
  • LMLaura C. Meurer
    Laura C. Meurer
  • RTRichard L. Tolman
    Richard L. Tolman
  • WGWilliam J. Greenlee
    William J. Greenlee
  • APArthur A. Patchett
    Arthur A. Patchett
  • RLRobert J. Lynch
    Robert J. Lynch
  • TSTerry W. Schorn
    Terry W. Schorn
  • JSJohn F. Strouse
    John F. Strouse
  • PSPeter K. S. Siegl
    Peter K. S. Siegl
Publisher website
Google Scholar
Abstract
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.