New potential renin inhibitors with dipeptide replacements in the molecule.
A series of eight non-peptidic potential renin inhibitors have been designed and synthesized. All of them contain dipeptide replacement: (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA) in their molecules. Four among them comprise two additional analogs of dipeptide: (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA) and (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (statine, Sta). All of the synthesized compounds contain also hydrophobic portions to receive a moderate lipophilicity of the molecules. Inhibitory activity of the compounds was measured in vitro by I-IPLC determination of Leu-Val-Tyr-Ser released from the N-acetyltetradecapeptide substrate by renin in the presence of the inhibitor. Asp-alpha(OEt)-(S,S)-ACHPA-epsilonAhx-Iaa (23) shows inhibitory activity (7%) at the concentration of 1.0 x 10(-2) M. The other synthesized compounds show no inhibitory activity up to this concentration.
Winiecka
Iwona
I
Department of Drug Chemistry, Medical University of Warsaw, Banacha 1, 02-097 Warszawa, Poland.
Dudkiewicz-Wilczyńska
Jadwiga
J
Roman
Iza
I
Paruszewski
Ryszard
R
D000215:Acylation; D000577:Amides / Q000138:chemical synthesis; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology*; D004952:Esters / Q000138:chemical synthesis; D006868:Hydrolysis; D007202:Indicators and Reagents; D012083:Renin / Q000737:chemistry; D012997:Solvents; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000577:Amides; D004151:Dipeptides; D004952:Esters; D007202:Indicators and Reagents; D012083:Renin; D012997:Solvents; D000092502:Renin Inhibitors