title: Synthesis and structure activity relationships of novel non-peptidic metallo-aminopeptidase inhibitors.
abstract: Racemic derivatives of 3-amino-2-tetralone were synthesised and evaluated for their ability to inhibit metallo-aminopeptidase activities. New compounds substituted in position 2 by methyl ketone, substituted oximes or hydroxamic acids as well as heterocyclic derivatives were evaluated against representative members of zinc-dependent aminopeptidases: leucine aminopeptidase (E.C. 3.4.11.1), aminopeptidase-N (E.C. 3.4.11.2), Aeromonas proteolytica aminopeptidase (E.C. 3.4.11.10), and the aminopeptidase activity of leukotriene A(4) hydrolase (E.C. 3.3.2.6). Several compounds showed K(i) values in the low micromolar range against the 'one-zinc' aminopeptidases, while most of them were rather poor inhibitors of the 'two-zinc' enzymes. This interesting selectivity profile may guide the design of new, specific inhibitors of target mammalian aminopeptidases with one active site zinc.
authors.affiliation: Laboratoite de Chimie Organique et Bioorganique, UMR 7015, ENSCMu, F-68093 Mulhouse Cedex, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Albrecht
authors.forename: Albert
authors.initials: A
authors.lastname: Defoin
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Salomon
authors.forename: Céline
authors.initials: C
authors.lastname: Tarnus
authors.forename: Anders
authors.initials: A
authors.lastname: Wetterholm
authors.forename: Jasper Z
authors.initials: JZ
authors.lastname: Haeggström
mesh_terms: D000333:Aeromonas / Q000201:enzymology; D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D002417:Cattle; D004951:Esterification; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
chemical_list: D011480:Protease Inhibitors; D000626:Aminopeptidases