A novel amino-benzosuberone derivative is a picomolar inhibitor of mammalian aminopeptidase N/CD13

International audienceA 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. (C) 2011 Elsevier Ltd. All rights reserved

Enantioenriched Isoindolinones from Chiral Phase-Transfer-Catalyzed Intramolecular Aza-Michael Reactions

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Exploring S1 plasticity and probing S1′ subsite of mammalian aminopeptidase N/CD13 with highly potent and selective aminobenzosuberone inhibitors

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