Synthesis of human renin inhibitory peptides, angiotensinogen transition-state analogs containing a retro-inverso amide bond.
The experimental details for the synthesis of human renin inhibitors are described. In order to avoid metabolic degradation of the Phe-His (P3-P2) amide bond in transition-state analogs, structurally modified acyl residues (P4-P3) were incorporated into the inhibitors. Compound 1a, which contained 2-(1-naphthylmethyl)-3-(N-phenethylcarbamoyl)propionyl residue (P4-P3) with a retro-inverso amide bond, L-histidine, and norstatine isoamylamide residue (P1-P1) as a transition-state mimic, had potent human renin inhibitory activity, and it lowered blood pressure when administered orally to common marmosets.
Harada
H
H
Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., Nagano, Japan.
Iizuka
K
K
Kamijo
T
T
Akahane
K
K
Yamamoto
R
R
Nakano
Y
Y
Tsubaki
A
A
Kubota
T
T
Shimaoka
I
I
Umeyama
H
H
D000577:Amides; D000595:Amino Acid Sequence; D000808:Angiotensinogen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000577:Amides; D000808:Angiotensinogen; D000092502:Renin Inhibitors