Potent, low molecular weight renin inhibitors containing a C-terminal heterocycle: hydrogen bonding at the active site.
A series of low-nanomolar renin inhibitors containing novel C-terminal heterocycles has been designed by formally cyclizing the C-terminus of a glycol-based inhibitor to the second hydroxyl. Molecular modeling suggests that the heterocyclic oxygen hydrogen bonds as an acceptor to the flap region of renin and that the second hydroxyl in the glycol-based inhibitors behaves similarly.
Abbott Laboratories, Cardiovascular Research Division, Abbott Park, Illinois 60064.
S H
SH
Rosenberg
J F
JF
Dellaria
D J
DJ
Kempf
C W
CW
Hutchins
K W
KW
Woods
R G
RG
Maki
E
E
de Lara
K P
KP
Spina
H H
HH
Stein
J
J
Cohen
D002219:Carbamates / Q000138:chemical synthesis / Q000494:pharmacology*; D055598:Chemical Phenomena; D002621:Chemistry; D005663:Furans / Q000138:chemical synthesis / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D006860:Hydrogen Bonding; D007783:Lactones / Q000138:chemical synthesis / Q000494:pharmacology*; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D002219:Carbamates; D005663:Furans; D006571:Heterocyclic Compounds; D007783:Lactones; D000092502:Renin Inhibitors; C018674:tetrahydrofuran