Ketomethylureas. A new class of angiotensin converting enzyme inhibitors.
The design rationale for a new series of tripeptide derived angiotensin converting enzyme (ACE) inhibitors, which we term "ketomethylureas", is described. Analogs of tripeptide substrates (i.e. N-benzoyl-Phe-Ala-Pro) in which the nitrogen atom of the scissile amide bond and the adjacent asymmetric carbon atom of the penultimate amino acid residue are formally transposed give rise to this novel class of inhibitors. The most potent ketomethylureas inhibit ACE with I50 values in the nM range.
Natarajan
S
S
Squibb Institute for Medical Research, Princeton, New Jersey 08540.
Gordon
E M
EM
Sabo
E F
EF
Godfrey
J D
JD
Weller
H N
HN
Pluscec
J
J
Rom
M B
MB
Engebrecht
J
J
Cushman
D W
DW
Deforrest
J M
JM
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis*; D000818:Animals; D007202:Indicators and Reagents; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D008782:Methylurea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D000806:Angiotensin-Converting Enzyme Inhibitors; D007202:Indicators and Reagents; D007659:Ketones; D008782:Methylurea Compounds; D009842:Oligopeptides