Studies directed toward the design of orally active renin inhibitors. 1. Some factors influencing the absorption of small peptides.
A systematic evaluation of structure-absorption relationships using a high throughput intraduodenal rat screening model has led to the delineation of a set of structural parameters that appear to govern bioavailability in a series of peptide-based renin inhibitors. Optimum structures, exemplified by 25 and 41, incorporated a single, solubilizing substituent at the C- or N-terminus combined with a lipophilic P2-site residue. Both inhibitors gave unprecedented plasma drug levels upon intraduodenal administration to monkeys, and the calculated bioavailability for 41 (14 +/- 4%) is the highest reported for any peptidic renin inhibitor.
Rosenberg
S H
SH
Abbott Laboratories, Cardiovascular Research Division, Abbott Park, Illinois 60064.
Spina
K P
KP
Woods
K W
KW
Polakowski
J
J
Martin
D L
DL
Yao
Z
Z
Stein
H H
HH
Cohen
J
J
Barlow
J L
JL
Egan
D A
DA
D000818:Animals; D001682:Biological Availability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004151:Dipeptides / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D015195:Drug Design; D004386:Duodenum / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D007408:Intestinal Absorption; D015394:Molecular Structure; D010080:Oxazoles / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D004151:Dipeptides; D010080:Oxazoles; D010455:Peptides; D010879:Piperazines; D000092502:Renin Inhibitors; C080797:5,8-diaza-10,11-dihydroxy-9-cyclohexylmethyl-13-methyl-1-(4-methylpiperazin-1-yl)-3-phenylmethyl-6-(thiazol-4-ylmethyl)tetradecane-1,4,7-trione; C080803:N-(2-((1-(cyclohexylmethyl)-2-(3-ethyl-2-oxo-5-oxazolidinyl)-2-hydroxyethyl)amino)-2-oxo-1-(2-thienylmethyl)ethyl)-gamma-oxo-alpha-(phenylmethyl)-4-morpholinebutanamide