Azido glycols: potent, low molecular weight renin inhibitors containing an unusual post scissile site residue.
Azidomethyl-substituted 1,2- and 1,3-diols were prepared from Boc-cyclohexylalanal and evaluated as transition state analogue renin inhibitors, leading to the development of a small (MW less than 600), nanomolar inhibitor. Remarkable aqueous solubility enhancement followed the incorporation of an N-terminal urea functionality. Evaluation of selected compounds both in vivo and in vitro demonstrated that while transport across the intestine occurred upon id administration, extensive liver extraction resulted in low systemic levels.
Rosenberg
S H
SH
Abbott Laboratories, Cardiovascular Research Division, Abbott Park, Illinois 60064.
Woods
K W
KW
Kleinert
H D
HD
Stein
H
H
Nellans
H N
HN
Hoffman
D J
DJ
Spanton
S G
SG
Pyter
R A
RA
Cohen
J
J
Egan
D A
DA
D000818:Animals; D001386:Azides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001692:Biological Transport; D055598:Chemical Phenomena; D002621:Chemistry; D006018:Glycols / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D008970:Molecular Weight; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D001386:Azides; D006018:Glycols; D000092502:Renin Inhibitors