Iwona Winiecka, Dorota Marszałek, Anna Goldnik, Paweł Jaworski, Aleksander P. Mazurek

New renin inhibitors containing phenylalanylhistidyl-y-amino acid derivatives in P3 – P1’ position.
2014-02-17

Abstract: Five potential inhibitors of renin have been designed and obtained. In the molecule position P3 ñ P1í, crucial for indicating inhibitory activity, all contain phenylalanylhistidylaminoalcanoyl group, ready for interaction with the hydrophobic pocket S3 ñ S1 of renin molecule. The aminoalcanoyl fragment consists of pseudodipeptidic units derivative of γ-amino acids: of 4-amino-3-hydroxybutanoic acid (AHBA) [26], 4-amino-5-(4-ethoxyphenyl)-3-hydroxypentanoic acid (AEPHPA) [13], 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA) (1) and 4-amino-3-hydroxynonanoic acid (AHNA) [21]. At the P3 ñ P2 position of obtained compounds an unnatural fragment, derivative of Phe-His dipeptide, was placed ande isoamyl amid of 6-aminohexanoic acid was attached at the end of the molecule (εAhx-Iaa). The preliminary in vitro tests indicated that all compounds were inactive. However, they provided valuable information on P3-P2 fragment possible structure modification able to produce a resonable renin activity inhibition. All synthesized inhibitors were chymotrypsin-resistant.

Keywords: renin inhibitors, hydrophobic pocket, position P3 - P1í, inhibitory activity, pseudodipeptide unit, γ-amino acid.