RESUMO
In order to probe the S1 and S1' 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 Ki values in the nanomolar range.
Assuntos
Aminobenzoatos/síntese química , Benzocicloeptenos/síntese química , Antígenos CD13/antagonistas & inibidores , Inibidores de Proteases/síntese química , Aminobenzoatos/química , Animais , Benzocicloeptenos/química , Antígenos CD13/química , Antígenos CD13/isolamento & purificação , Rim/química , Rim/enzimologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteases/química , Estereoisomerismo , Relação Estrutura-Atividade , Suínos , TermodinâmicaRESUMO
Racemic trisubstituted benzocycloheptanes were synthesized and evaluated for their ability to inhibit metalloaminopeptidase activities. A highly selective nanomolar inhibitor of a prototypical 'two zinc' aminopeptidase from the M28 family was observed with these tridentate species, while bidentate analogs proved to be highly selective for the 'one zinc' M1 family of enzymes. The selectivity profile of these new, low molecular weight structures may guide the design of specific, non-peptidic inhibitors of binuclear aminopeptidases.
Assuntos
Aminopeptidases/antagonistas & inibidores , Benzocicloeptenos/química , Inibidores de Proteases/síntese química , Aeromonas/enzimologia , Aminopeptidases/metabolismo , Benzocicloeptenos/síntese química , Benzocicloeptenos/metabolismo , Sítios de Ligação , Domínio Catalítico , Escherichia coli/enzimologia , Simulação de Acoplamento Molecular , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Ligação Proteica , Relação Estrutura-Atividade , Zinco/químicaRESUMO
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.
