Université de Haute Alsace, Laboratoire de Chimie Organique et Bioorganique, EA4466 ENSCMu, 3, rue Alfred Werner, F-68093, Mulhouse Cedex, France.
Bioorg Med Chem. 2011 Sep 15;19(18):5716-33. doi: 10.1016/j.bmc.2011.06.089. Epub 2011 Jul 19.
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.
本文描述了一类新型的低分子量、高活性和选择性的氨肽酶 N（APN/CD13）非肽类抑制剂。我们报告了 7-氨基苯并环庚烯-6-酮 1a 的外消旋取代类似物的合成和体外评价。我们研究了芳环上带有苯基和卤素取代基的各种取代基。体外动力学研究表明，这些化合物是迄今为止发现的最有效的 APN/CD13 抑制剂之一。在环己烯酮 1a 的 1 位或 4 位上引入疏水性取代基，得到了具有纳摩尔级 K(i)值的强效化合物 1c-h、b'-c'、f'、h'。本工作的关键发现是观察到 1,4-二取代的加和效应，导致发现了对映体抑制剂 1d'（K(i)=60 pM）。设计的抑制剂保留了我们的先导化合物 1a 对选择的氨肽酶家族成员的选择性，同时显著提高了抑制活性和稳定性。
