Amino-benzosuberone: a novel warhead for selective inhibition of human aminopeptidase-N/CD13.

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Albrecht S, Al-Lakkis-Wehbe M, Orsini A, Defoin A, Pale P, Salomon E, Tarnus C, Weibel JM

Amino-benzosuberone: a novel warhead for selective inhibition of human aminopeptidase-N/CD13.

Bioorg Med Chem. 2011 Feb 15;19(4):1434-49. doi: 10.1016/j.bmc.2011.01.008. Epub 2011 Jan 11.

PubMed ID
21292493 [ View in PubMed
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Abstract

This paper describes the design and synthesis of compounds belonging to a novel class of highly selective mammalian CD13 inhibitors. Racemic homologues of 3-amino-2-tetralone 1 were synthesised and evaluated for their ability to selectively inhibit the membrane-bound, zinc-dependent aminopeptidase-N/CD13 (EC 3.4.11.2). Some of these novel non-peptidic compounds are potent, competitive inhibitors of the mammalian enzyme, with K(i) values in the low micromolar range in spite of their minimal size (MW <200 Da). Moreover, they show an interesting selectivity profile against representative members of the aminopeptidase family, that is leucine aminopeptidase (EC 3.4.11.1), Aeromonas proteolytica aminopeptidase (EC 3.4.11.10) and the aminopeptidase activity of leukotriene A4 hydrolase (EC 3.3.2.6). The amino-benzosuberone derivative 4 is the most promising compound in terms of potency, stability and selectivity. A hypothetical binding mode of 4 to the catalytic zinc and several conserved active site residues is proposed, based on the observed structure-activity relationships, structural insights from aminopeptidase-N homologues of known three-dimensional structure.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
UbenimexLeukotriene A-4 hydrolaseIC 50 (nM)500N/AN/ADetails