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
Covalent ligand-target interactions offer significant pharmacological advantages. However, off-target reactivity of the reactive groups, which usually have electrophilic properties, must be minimized, and the selectivity of irreversible inhibitors is a crucial requirement. We therefore performed a systematic study to determine the selectivity of several electrophilic groups that can be used as building blocks for covalently binding ligands. Six reactive groups with modulated electrophilicity were combined with 11 nonreactive moieties, resulting in a small combinatorial library of 72 fragment-like compounds. These compounds were screened against a group of 11 enzyme targets to assess their selectivity and their potential for promiscuous binding to proteins. The assay results showed a considerably lower degree of promiscuity than initially expected, even for those members of the screening collection that contain supposedly highly reactive electrophiles.
Assuntos
Biologia Computacional , Elétrons , Inibidores Enzimáticos/metabolismo , Enzimas/metabolismo , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Enzimas/química , Células HeLa , Humanos , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Especificidade por SubstratoRESUMO
AIM: To determine the pharmacokinetics, safety and performance of a novel matrix formulation of fentanyl. METHODS: Transdermal fentanyl was administered as the novel matrix and the Durogesic reservoir formulations (24 subjects, 100 microg h(-1)) in a randomized, fully replicate, four-way crossover study. Serum concentrations of fentanyl were assayed by LC/MS/MS. Pharmacokinetic parameters of fentanyl and performance (adherence and skin irritability) were evaluated. RESULTS: Test/reference ratio (90% confidence intervals) for AUC(0-t), AUC(inf) and C(max) were 105.5% (99.4, 112.0), 105.3% (99.3, 111.6) and 111.4% (100.4, 123.6), respectively. Adherence and skin irritability results of the two formulations were similar. CONCLUSION: The two formulations are expected to result in similar efficacy for the management of severe pain.