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Novel renin inhibitors containing a non-peptide aminoalkanoyl moiety at P1-P1' position
I. Winiecka , D. Marszałek , A. Goldnik , P. Jaworski , A.P. Mazurek
Article Info
Abstract
Six novel potential renin inhibitors have been designed and synthesized. All these inhibitors contained an unnatural aminoalkanoyl moiety at the central position P1-P1' of the molecule, which is attacked by renin. The moiety consists of pseudodipeptidic units, transition state analogues of a natural dipeptide of the parent substance: 4-amino-3-hydroxybutanoic acid (AHBA), 4-amino-5-(4-ethoxyphenyl)-3-hydroxypentanoic acid (AEPHPA), 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA) or 4-amino-3-hydroxynonanoic acid (AHNA). An unnatural moiety, 4-methoxyphenylalanylhistydyl (Phe(4-OMe)-His) has been introduced at the P3-P2 position of the obtained compounds. Five compounds contain isoamylamide of 6-aminohexanoic acid (ε-Ahx-Iaa) at the P2'–P3' position. One of designed inhibitors has been obtained in the form of an ethyl ester. The in vitro renin inhibitory activity of all synthesized compounds is contained within the range 10–6 – 10–8 M. The compound in the form of an ethyl ester has proven to be the most active (IC50 = 1.3 × 10–8 M) but also susceptible to enzymatic degradation. The other five inhibitors were stable to chymotrypsin.