N-(α-Hydroxyalkanoyl) Derivatives of Leu-Val-Phe-OCH₃as Inhibitors of Renin

The following N-(α-hydroxyalkanoyl) derivatives of Leu-Val-Phe-OCH3 were synthesized and tested for their ability to inhibit human amniotic renin: D- and L-α-hydroxyisocaproyl-Leu-Val-Phe-OCH₃, D- and L-α-hydroxvisovaleryl-Leu-Val-Phe-OCH₃, L-2-hydroxy-3-phenylpropanoyl-Leu-Val-Phe-OCH₃, and D- and L-α-hydroxyphenylacetyl-Leu-Val-Phe-OCH₃. Analysis of the compounds through the use of Dixon plots showed all of the compounds to be competitive inhibitors of renin. All but D-α-hydroxyisovaleryl-Leu-Val-Phe-OCH₃were found to be more active than the known tetrapeptide inhibitor Leu-Leu-Val-Phe-OCH₃(1). The two most active compounds of the series were L-α-hydroxyisocaproyl-Leu-Val-Phe-OCH₃(K_i= 0.23 mM) and L-α-hydroxyisovaleryl-Leu-Val-Phe-OCH₃(K_i= 0.3 mM).