Renin Inhibitors. Substitution of the Leucyl Residues of Leu-Leu-Val-Phe-OCH₃ with 3-Amino-2-hydroxy-5-methylhexanoic Acid

The 2S,3S and 2R,3S diastereoisomers of the hydroxy amino acid 3-amino-2-hydroxy-5-methylhexanoic acid (AHMHA) were synthesized and substituted for the leucyl residues of Leu-Leu-Val-Phe-OCH₃ to yield the following analogues: AHMHA-Leu-Val-Phe-OCH₃, AHMHA-Val-Phe-OCH₃, and Leu-AHMHA-Val-Phe-OCH₃. These analogues were tested in vitro for their ability to inhibit human amniotic renin. All of the analogues were found to inhibit renin to some extent with inhibitory constants in the range of 10⁻³ to 10⁻⁴ M. The analogues AHMHA-Leu-Val-Phe-OCH₃ and AHMHA-Val-Phe-OCH₃ exhibited competitive inhibition when the 2S,3S isomer of AHMHA was employed and noncompetitive kinetics when the 2R,3S isomer of AHMHA was used. For the Leu-AHMHA-Val-Phe-OCH₃ analogues, competitive kinetics were observed regardless of the isomer of AHMHA employed. These latter analogues also proved to be the most active in the above series.