title: Amino-benzosuberone: a novel warhead for selective inhibition of human aminopeptidase-N/CD13.
abstract: This paper describes the design and synthesis of compounds belonging to a novel class of highly selective mammalian CD13 inhibitors. Racemic homologues of 3-amino-2-tetralone 1 were synthesised and evaluated for their ability to selectively inhibit the membrane-bound, zinc-dependent aminopeptidase-N/CD13 (EC 3.4.11.2). Some of these novel non-peptidic compounds are potent, competitive inhibitors of the mammalian enzyme, with K(i) values in the low micromolar range in spite of their minimal size (MW <200 Da). Moreover, they show an interesting selectivity profile against representative members of the aminopeptidase family, that is leucine aminopeptidase (EC 3.4.11.1), Aeromonas proteolytica aminopeptidase (EC 3.4.11.10) and the aminopeptidase activity of leukotriene A4 hydrolase (EC 3.3.2.6). The amino-benzosuberone derivative 4 is the most promising compound in terms of potency, stability and selectivity. A hypothetical binding mode of 4 to the catalytic zinc and several conserved active site residues is proposed, based on the observed structure-activity relationships, structural insights from aminopeptidase-N homologues of known three-dimensional structure.
authors.affiliation: Laboratoire de Chimie Organique et Bioorganique, FRE3252, ENSCMu, F-68093 Mulhouse Cedex, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Albrecht
authors.forename: Mira
authors.initials: M
authors.lastname: Al-Lakkis-Wehbe
authors.forename: Alban
authors.initials: A
authors.lastname: Orsini
authors.forename: Albert
authors.initials: A
authors.lastname: Defoin
authors.forename: Patrick
authors.initials: P
authors.lastname: Pale
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Salomon
authors.forename: Céline
authors.initials: C
authors.lastname: Tarnus
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Weibel
mesh_terms: D000840:Anisoles / Q000737:chemistry* / Q000494:pharmacology; D018826:CD13 Antigens / Q000037:antagonists & inhibitors*; D003508:Cycloheptanes / Q000737:chemistry* / Q000494:pharmacology; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D012997:Solvents / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000840:Anisoles; D003508:Cycloheptanes; D011480:Protease Inhibitors; D012997:Solvents; C558240:amino-benzosuberone; D018826:CD13 Antigens