3-Amino-2-tetralone derivatives: novel potent and selective inhibitors of aminopeptidase-M (EC 3.4.11.2).
Derivatives of 3-amino-2-tetralone were evaluated for their ability to selectively inhibit the membrane-bound zinc-dependent aminopeptidase (EC 3.4.11.2), isolated from porcine kidney. These novel nonpeptidic compounds are potent competitive inhibitors of the enzyme. Some of them have Ki values in the nanomolar range (g, Ki = 80 nM). Moreover, these inhibitors are selective for aminopeptidase-M (AP-M) since they do not inhibit aspartate aminopeptidase and arginine aminopeptidase and only poorly inhibit cytosolic leucine aminopeptidase at high concentrations (g, Ki = 70 microM). The availability of inhibitors which are selective for AP-M with respect to other mammalian aminopeptidases may aid in identifying new endogenous substrates and thus clarify the physiological or pathophysiological role(s) of AP-M.
Schalk
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Marion Merrell Dow Research Institute, Strasbourg, France.
d'Orchymont
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Jauch
M F
MF
Tarnus
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C
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001665:Binding Sites; D018826:CD13 Antigens; D007668:Kidney / Q000201:enzymology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D010455:Peptides; D013329:Structure-Activity Relationship; D013552:Swine; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000494:pharmacology*; D015032:Zinc / Q000378:metabolism
D000900:Anti-Bacterial Agents; D010455:Peptides; D013764:Tetrahydronaphthalenes; C016977:amastatin; D000626:Aminopeptidases; D018826:CD13 Antigens; D007930:Leucine; C012211:ubenimex; D015032:Zinc