Novel renin inhibitors containing analogues of statine retro-inverted at the C-termini: specificity at the P2 histidine site.
Substituted 1,3- and 1,4-diamines were prepared from epoxides derived from Boc-leucine or Boc-cyclohexylalanine. These diamines were incorporated into renin inhibitors (IC50 = 4-1500 nM) replacing the Leu-Val scissile bond in small peptide analogues of angiotensinogen. Replacement of the P2 histidine imidazole with other heterocycles maintained or enhanced binding while changing the overall basicity of the inhibitor. Finally, substitution of O-methyltyrosine for the P3 phenylalanine suppressed chymotrypsin cleavage of the P3-P2 bond.
Rosenberg
S H
SH
Plattner
J J
JJ
Woods
K W
KW
Stein
H H
HH
Marcotte
P A
PA
Cohen
J
J
Perun
T J
TJ
D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D002918:Chymotrypsin / Q000494:pharmacology; D003959:Diamines / Q000138:chemical synthesis / Q000494:pharmacology; D006639:Histidine; D006801:Humans; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000596:Amino Acids; D002918:Chymotrypsin; D003959:Diamines; D006639:Histidine; D000092502:Renin Inhibitors; C013165:statine