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

In order to probe the S1 and S10 mammalian aminopeptidase N subsites, racemic 1- or 4-substituted 7-aminobenzocyclohepten-6-one derivatives were synthesized and evaluated for their ability to inhibit mammalian aminopeptidase N. We focused on improving the physicochemical and ADME properties of this series by targeting lipophilicity and LELP score. Some 4-heteroaryl substituted analogues displayed reduced lipophilicity and enhanced inhibition potency with K-i values in the nanomolar range. (C) 2015 Elsevier Ltd. All rights reserved.