title: Novel renin inhibitors containing a non-peptide aminoalkanoyl moiety at P1-P1' position.
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 (epsilon-Ahx-laa) 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 x 10(-8) M) but also susceptible to enzymatic degradation. The other five inhibitors were stable to chymotrypsin.
authors.forename: I
authors.initials: I
authors.lastname: Winiecka
authors.forename: D
authors.initials: D
authors.lastname: Marszałek
authors.forename: A
authors.initials: A
authors.lastname: Goldnik
authors.forename: P
authors.initials: P
authors.lastname: Jaworski
authors.forename: A P
authors.initials: AP
authors.lastname: Mazurek
mesh_terms: D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D002918:Chymotrypsin / Q000737:chemistry; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology; D006868:Hydrolysis; D007202:Indicators and Reagents; D010455:Peptides; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D002918:Chymotrypsin; D004151:Dipeptides; D004952:Esters; D007202:Indicators and Reagents; D010455:Peptides; D000092502:Renin Inhibitors