New fluoroketones as human renin inhibitors.
Renin inhibition has been evaluated for a new class of fluorinated ketones, true analogues of peptides that have been retroinverted at the C-terminal position. The readily formed hydrate of the ketone is proposed to mimic the tetrahedral intermediate that occurs during the enzyme-catalyzed hydrolysis of amide linkage. From this series of compounds it appears that the number of reverted amide bonds is crucial in terms of activity. Furthermore, a shortening of the C-terminal part of our peptide analogues and the replacement of the leucine residue in P1 by a cyclohexylalanine leads to the tripeptide analogue 12 a potent renin inhibitor (IC50 = 3.5 x 10(-9) M).
Tarnus
C
C
Merrell Dow Research Institute, Strasbourg Center, France.
Jung
M J
MJ
Rémy
J M
JM
Baltzer
S
S
Schirlin
D G
DG
D015195:Drug Design; D006801:Humans; D007659:Ketones / Q000494:pharmacology; D015394:Molecular Structure; D009842:Oligopeptides / Q000494:pharmacology; D012083:Renin / Q000097:blood; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D007659:Ketones; D009842:Oligopeptides; D012083:Renin; D000092502:Renin Inhibitors