Water-soluble renin inhibitors: design of a subnanomolar inhibitor with a prolonged duration of action.
Incorporation of nonreactive polar functionalities at the C- and N-termini of renin inhibitors led to the development of a subnanomolar compound (21) with millimolar solubility. This inhibitor demonstrated excellent efficacy and a long duration of action upon intravenous administration to monkeys. While activity was also observed intraduodenally, a comparison of the blood pressure responses indicated low bioavailability. Subsequent experiments in rats showed that, although the compound was absorbed from the gastrointestinal tract, extensive liver extraction severely limited bioavailability.
Rosenberg
S H
SH
Abbott Laboratories, Cardiovascular Research Division, Abbott Park, Illinois 60064.
Woods
K W
KW
Sham
H L
HL
Kleinert
H D
HD
Martin
D L
DL
Stein
H
H
Cohen
J
J
Egan
D A
DA
Bopp
B
B
Merits
I
I
D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D008252:Macaca fascicularis; D008297:Male; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D000092502:Renin Inhibitors
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D009842:Oligopeptides; D000092502:Renin Inhibitors