NEW INHIBITORS OF RENIN THAT CONTAIN NOVEL PHOSPHOSTATINE LEU-VAL REPLACEMENTS

A novel series of renin inhibitors based on the Phe8-His9-Leu10-Val11substructure of reinin's natural substrate, angiotensinogen, is reported. These inhibitors retain the Phe8-His9portion of the native substructure and employ novel phosphostatine Leu10-Val11replacements (LVRs). The phosphostatine LVRswere prepared by condensing a dialkyl phosphonate ester stabilized anion with either AT-t-Boc-amino aldehydes or iV-tritylamino aldehydes (derived from the corresponding amino acid). Structure-activity relationships at the Leu10side chain revealed that the LVR derived from L-cyclohexylalanine provided a 130-fold boost in potency over the LVR derived from L-leucine. The dialkyl ester moiety was varied and a loss in potency was incurred when the alkyl ester was chain extended or α-branched; dimethyl esters provided optimum potency. The phosphonate moiety was replaced by a half-acid half-ester phosphonate and dimethylphosphinate; both replacements lead to a loss in potency. The more potent inhibitors (IC50=20-50 nM) were found to be selective inhibitors for renin over porcine pepsin and bovine cathepsin D (little or no inhibition was observed at 10-5M). © 1990, American Chemical Society. All rights reserved.