Abstract
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.
MeSH terms
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Animals
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Biological Availability
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Chemical Phenomena
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Chemistry, Physical
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Dipeptides / chemistry
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Dipeptides / pharmacokinetics*
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Dipeptides / pharmacology
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Drug Design*
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Duodenum / metabolism
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Haplorhini
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Humans
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Intestinal Absorption*
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Molecular Structure
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Oxazoles / chemistry
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Oxazoles / pharmacokinetics*
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Oxazoles / pharmacology
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Peptides / chemistry
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Peptides / pharmacokinetics*
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Peptides / pharmacology
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Piperazines / chemistry
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Piperazines / pharmacokinetics*
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Piperazines / pharmacology
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Rats
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Renin / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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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
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Dipeptides
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Oxazoles
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Peptides
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Piperazines
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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
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Renin