Cyclic peptide inhibitors of human renin based on a linear peptide, Boc-D-Phe-Cys(Acm)-D-Trp-Leu-OMe (1), were prepared by solution-phase methods. Potent inhibitors were obtained in one series of compounds, Z-Glu-D-Phe-Lys-D-Trp-Leu-OMe (3), in which the D-phenylalanine residue was incorporated in a 15-membered ring structure. Any reductions or enlargements of the ring size led to inactive or less potent peptides. The most potent inhibitor of human renin, Me3CCH2-Glu-D-Phe-Lys-D-Trp-NH(CH2)2CHMe2 (31) (IC50 6.3 x 10(-8) M), was obtained by changing N- and C-terminal parts of pentapeptide 3. It was about 650-fold more potent than linear tetrapeptide I and about 50-fold more potent than cyclic peptide 3. Compound 31 was also 112-fold more potent against human renin than against porcine renin.