New renin inhibitors containing phenylalanylhistidyl-gamma-amino acid derivatives in P3 - P1' position.
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.
Iwona
I
Winiecka
Dorota
D
Marszałek
Anna
A
Goldnik
Paweł
P
Jaworski
Aleksander P
AP
Mazurek
D004151:Dipeptides; D057927:Hydrophobic and Hydrophilic Interactions; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D004151:Dipeptides; D000092502:Renin Inhibitors; C022144:histidylphenylalanine