title: A novel amino-benzosuberone derivative is a picomolar inhibitor of mammalian aminopeptidase N/CD13.
abstract: A new class of low molecular weight, highly potent and selective non peptidic inhibitors of aminopeptidase N (APN/CD13) is described. We report the synthesis and in vitro evaluation of racemic substituted analogues of 7-amino-benzocyclohepten-6-one 1a. We investigated various substitutions on the aromatic ring with phenyl and halogen groups. In vitro kinetic studies revealed that these compounds are among the most effective APN/CD13 inhibitors found so far. Hydrophobic substituents placed at position 1 or 4 on the cycloheptenone 1a led to the potent compounds 1c-h,b'-c',f',h' with K(i) in the nanomolar range. The key finding of the present work was the observed additive effect of 1,4-disubstitutions which led to the discovery of the picomolar inhibitor 1d' (K(i)=60 pM). The designed inhibitors retain the selectivity of our lead structure 1a towards selected members of the aminopeptidase family, combined with an impressive increase in inhibitory potency and a conserved stability.
authors.affiliation: Université de Haute Alsace, Laboratoire de Chimie Organique et Bioorganique, EA4466 ENSCMu, 3, rue Alfred Werner, F-68093, Mulhouse Cedex, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Maiereanu
authors.forename: Céline
authors.initials: C
authors.lastname: Schmitt
authors.forename: Nadège
authors.initials: N
authors.lastname: Schifano-Faux
authors.forename: Didier
authors.initials: D
authors.lastname: Le Nouën
authors.forename: Albert
authors.initials: A
authors.lastname: Defoin
authors.forename: Céline
authors.initials: C
authors.lastname: Tarnus
mesh_terms: D000333:Aeromonas / Q000201:enzymology; D000818:Animals; D000840:Anisoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018826:CD13 Antigens / Q000037:antagonists & inhibitors*; D003508:Cycloheptanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D000840:Anisoles; D003508:Cycloheptanes; D004791:Enzyme Inhibitors; C558240:amino-benzosuberone; D018826:CD13 Antigens