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

• Published in: Bioorganic & medicinal chemistry Vol. 19; no. 4; pp. 1434 - 1449
• Main Authors: Albrecht, Sébastien, Al-Lakkis-Wehbe, Mira, Orsini, Alban, Defoin, Albert, Pale, Patrick, Salomon, Emmanuel, Tarnus, Céline, Weibel, Jean-Marc
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.02.2011; Elsevier
• Subjects: active sites; Aeromonas proteolytica; Aminobenzoheptenone; Aminopeptidase-N inhibitor; Analytical, structural and metabolic biochemistry; Anisoles - chemistry; Anisoles - pharmacology; APN/CD13; Biological and medical sciences; CD13 Antigens - antagonists & inhibitors; Chemical Sciences; Cycloheptanes - chemistry; Cycloheptanes - pharmacology; Dimerization; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Hydrolases; leucyl aminopeptidase; Medical sciences; membrane alanyl aminopeptidase; Miscellaneous; Models, Molecular; Molecular Structure; Organic chemistry; Pharmacology. Drug treatments; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Solvents - chemistry; Stereoisomerism; Structure-Activity Relationship; structure-activity relationships; Vibrio proteolyticus; zinc; Aminobenzoheptenone; APN/CD13; Aminopeptidase-N inhibitor; Human; Enzyme; Aminopeptidases; Enzyme inhibitor; Selectivity; In vitro; Peptidases; Aminoketone; Position isomer; Structure activity relation; Bicyclic compound; Hydrolases; Aromatic compound; Chemical synthesis; Membrane alanyl aminopeptidase; selective inhibition of human; aminopeptidase-N/CD13; Amino-benzosuberone
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.01.008

Racemic aminoindanone 2, amino benzosuberones 3, 4, and aminocycloheptanone 5 were synthesised and evaluated as inhibitors of four representative members of zinc-dependent aminopeptidases. Ki values in the low micromolar range against ‘one zinc’ aminopeptidases are obtained. The stability of these compounds was studied. 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 Ki values in the low micromolar range in spite of their minimal size (MW <200Da). 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.