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

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• 作者：Carmen  ; Maiereanu^a ; Cé ; line  ; Schmitt^a ; Nadè ; ge  ; Schifano-Faux^b ; Didier  ; Le Nouë ; n^a ; Albert  ; Defoin^a ;   ; ^{Albert.Defoin@uha.fr} ; Cé ; line  ; Tarnus^a ;   ; ^{Celine.Tarnus@uha.fr}
• 关键词：Aminobenzoheptenone ; Aminopeptidase-N inhibitor ; APN/CD13
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2011
• 出版时间：15 September 2011
• 年：2011
• 卷：19
• 期：18
• 页码：5716-5733
• 全文大小：623 K

文摘

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¨Ch,b?b xmlns="""">¨Cc?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.