N-(.alpha.-hydroxyalkanoyl) derivatives of Leu-Val-Phe-OCH3 as inhibitors of renin

Abstract

The following N-(alpha-hydroxylakanoyl) derivatives of Leu-Val-Phe-OCH3 were synthesized and tested for their ability to inhibit human amniotic renin: D- and L-alpha-hydroxyisocaproyl-Leu-Val-Phe-OCH3, D- and L-alpha-hydroxyisovaleryl-Leu-Val-Phe-OCH3, L-2-hydroxy-3-phenylpropanoyl-Leu-Val-Phe-OCH3, and D- and L-alpha-hydroxyphenylacetyl-Leu-Val-Phe-OCH3. Analysis of the compounds through the use of Dixion plots showed all of the compounds to be competitive inhibitors of renin. All but D-alpha-hydroxyisovaleryl-Leu-Val-Phe-OCH3 were 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-alpha-hydroxyisocaproyl-Leu-Val-Phe-OCH3 (Ki = 0.23 mM) and L-alpha-hydroxyisovaleryl-Leu-Val-Phe-OCH3 (Ki = 0.3 mM).

Modular Evolution of a Chiral Auxiliary for the 1,3-Dipolar Cycloaddition of Isomünchnones with Vinyl Ethers

“…To better understand how amino acid substitution affects the level of diastereofacial induction, a series of α-hydroxy acids, readily accessible from their corresponding α-amino acids, were used to construct α-diazoimides with incremental substitution. In analogy with the parent system 12 , four diazo substrates, 14 , 16 , 18 , and 21 , were prepared from l -alanine, l -leucine, l -phenylalanine, and l - tert -leucine, respectively .…”