Modified heterocyclic phenylalanine analogues designed as replacements for the P3-P4 region were synthesized and incorporated into renin inhibitors. These inhibitors were found to have significant activity versus human recombinant renin, as well as in vivo activity. The compounds proved to be very resistant to chymotrypsin degradation, as exemplified by compound 8, which remained greater than 60% intact after a 24-h exposure to chymotrypsin. In contrast, the Boc-Phe analogue was nearly completely degraded after 1 h. Compound 6 proved to be the most potent renin inhibitor with an IC50 = 8.9 nM. These stable cyclized phenylalanines should prove to be generally useful as a substitute for Boc-Phe in protease inhibitors.