Statine-Containing Dipeptide and Tripeptide

SUMMARY Dipeptide and tripeptide derivatives containing a statine residue were synthesized as inhibitors of human renin. ES-305, bis[(l-naphthyl)methyl]acetyl(BNMA)-histidyl-statine 2(S)-meth-ylbutylamide was found to be a highly potent inhibitor of human renin with a K, value of 1.7 x 1 0 ' M. Dipeptide derivatives with the BNMA group at the jV-terminal (BNMA-VaJ-Sta-isoleucinol [ES-313], BNMA-Leu-Sta-isoleucinol [ES-316], and BNMA-Nle-Sta-isoleucinol [ES-317]) had potencies against human renin that were similar to the potency of ES-305. All these dipeptide derivatives competitively inhibited human renin. The inhibitors were also potent against monkey renin but were less effective against renins from pig, goat, dog, rabbit, and rat. ES-305 had little effect on cathepsin D and pepsin at the concentration of 1 0 ' M. The other derivatives showed detectable inhibition of cathepsin D (ICW, 10-M0- ' M) and pepsin (lO-'-lO" ' M). All the compounds had little or no effect on trypsin, chymo-trypsin, angiotensin converting enzyme, and urinary kallikrein at the concentration of 10" ' M. Our results indicate that ES-305 is a highly potent and specific inhibitor of human renin. This compound is superior to other, previously described statine-containing renin inhibitors with respect to molecular size and enzyme specificity. (Hypertension 8 [Suppl II]: II-1-II-5, 1986) KEY WORDS • renin inhibitors • renal renin • plasma reni