Mercaptoacyl amino acid inhibitors of atriopeptidase. 1. Structure-activity relationship studies of methionine and S-alkylcysteine derivatives.
A broad series of N-(3-mercaptoacyl) amino acid derivatives was evaluated for their ability to inhibit atriopeptidase (neutral endopeptidase, EC 3.4.24.11) in vitro and in vivo. Structural parameters studied were (i) the substituent on the 2-position of the 3-mercaptopropionyl moiety, (ii) the amino acid component, (iii) the S-terminal derivative, and (iv) the C-terminal derivative. Optimum activity was observed for derivatives of methionine and S-alkylcysteines. N-[3-Mercapto-2(S)-[(2-methylphenyl)methyl]-1-oxopropyl]-L-methionine was identified as a highly effective inhibitor of atriopeptidase meriting evaluation as a potential cardiovascular therapeutic agent.
Neustadt
B R
BR
Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539.
Smith
E M
EM
Nechuta
T L
TL
Bronnenkant
A A
AA
Haslanger
M F
MF
Watkins
R W
RW
Foster
C J
CJ
Sybertz
E J
EJ
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives*; D008297:Male; D008715:Methionine / Q000737:chemistry*; D008969:Molecular Sequence Data; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000596:Amino Acids; D000959:Antihypertensive Agents; D002800:Cholinesterase Inhibitors; D009320:Atrial Natriuretic Factor; D008715:Methionine; D015260:Neprilysin; D003545:Cysteine