New inhibitors of renin that contain novel phosphostatine Leu-Val replacements

Article abstract of DOI:10.1021/jm00164a011

A novel series of renin inhibitors based on the Phe⁸-His⁹-Leu¹⁰-Val¹¹ substructure of renin's natural substrate, angiotensinogen, is reported. These inhibitors retain the Phe⁸-His⁹ portion of the native substructure and employ novel phosphostatine Leu¹⁰-Val¹¹ replacements (LVRs). The phosphostatine LVRs were prepared by condensing a dialkyl phosphonate ester stabilized anion with either N-t-Boc-amino aldehydes or N-tritylamino aldehydes (derived from the corresponding amino acid). Structure-activity relationships at the Leu¹⁰ side 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-branced; 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^-5 M).