Novel 3-amino-2-hydroxy acids containing protease inhibitors. Part 1: Synthesis and kinetic characterization as aminopeptidase P inhibitors.
Novel, potent inhibitors of aminopeptidase P, containing a 3-amino-2-hydroxy acid and a proline or a proline analogues, have been prepared. One part of the bestatin-derived inhibitors was found to inhibit APP from Escherichia coli and from rat intestine according to a mixed-type mechanism, with Ki values up to 1.26 microM. The other compounds, 3-amino-2-hydroxy acyl prolines of a different configuration, inhibit APP competitively, according to a slow-binding mechanism, with Ki values in the nanomolar up to the micromolar range.
Martin-Luther-University Halle-Wittenberg, Department of Biochemistry, Institute of Biochemistry/Biotechnology, Kurt-Mothes-Str.3, 06120 Halle/Saale, Germany. stoeckel@biochemtech.uni-halle.de
Angela
A
Stöckel-Maschek
Beate
B
Stiebitz
Regine
R
Koelsch
Klaus
K
Neubert
D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology*; D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D001665:Binding Sites; D004926:Escherichia coli / Q000187:drug effects; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
D000596:Amino Acids; D011480:Protease Inhibitors; D011758:Pyrroles; D013844:Thiazoles; D011392:Proline; D000626:Aminopeptidases; C022750:X-Pro aminopeptidase; D007930:Leucine; C012211:ubenimex