New renin inhibitors containing phenylalanylhistidyl-gamma-amino acid derivatives in P3 - P1' position

Acta Pol Pharm. 2014 Jan-Feb;71(1):59-69.

Abstract

Five potential inhibitors of renin have been designed and obtained. In the molecule position P3 - P1', crucial for indicating inhibitory activity, all contain phenylalanylhistidylaminoalcanoyl group, ready for interaction with the hydrophobic pocket S3 - S1 of renin molecule. The aminoalcanoyl fragment consists of pseudo-dipeptidic units derivative of gamma-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 - P2 position of obtained compounds an unnatural fragment, derivative of Phe-His dipeptide, was placed ande isoamyl amid of 6-amino-hexanoic acid was attached at the end of the molecule (epsilonAhx-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dipeptides
  • Hydrophobic and Hydrophilic Interactions
  • Renin / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Dipeptides
  • histidylphenylalanine
  • Renin