RESUMO
We report the design of novel, potent cPLA(2)α inhibitors that possess an α-methyl-2-ketothiazole that acts as a serine-reactive moiety. We describe the optimization of the series for potency and metabolic stability towards ketone reduction. This was achieved by attenuating the reactivity of the ketone using a combination of electronic and steric effects.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Fosfolipases A2 do Grupo IV/antagonistas & inibidores , Cetonas/química , Tiazóis/síntese química , Tiazóis/farmacologia , Animais , Estabilidade de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Células HL-60 , Humanos , Concentração Inibidora 50 , Cetonas/síntese química , Cetonas/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oxirredução , Ratos , Serina/química , Tiazóis/químicaRESUMO
By careful analysis of experimental X-ray ligand crystallographic protein data across several inhibitor series we have discovered a novel, potent and selective series of iNOS inhibitors exemplified by compound 8.
Assuntos
Inibidores Enzimáticos/química , Isoxazóis/química , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Piridinas/química , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Isoxazóis/síntese química , Isoxazóis/farmacologia , Camundongos , Microssomos Hepáticos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estrutura Terciária de Proteína , Piridinas/farmacologia , RatosRESUMO
The high lipophilicity of a series of cytosolic phospholipase A(2) inhibitors has been reduced by the modification of a decyloxyphenyl chain designed to mimic the arachidonyl group of the natural substrate. These changes have resulted in an improvement in the whole cell potency of the inhibitors.
Assuntos
Ácido Araquidônico/metabolismo , Citosol/química , Inibidores Enzimáticos/farmacologia , Fosfolipases A/antagonistas & inibidores , Ácido Araquidônico/química , Inibidores Enzimáticos/síntese química , Células HL-60 , Humanos , Concentração Inibidora 50 , Mimetismo Molecular , Fosfolipases A/metabolismo , Fosfolipases A2 , Relação Estrutura-AtividadeRESUMO
Using knowledge of the substrate specificity of cPLA(2) (phospholipases A(2)), a novel series of inhibitors of this enzyme were designed based upon a three point model of inhibitor binding to the enzyme active site comprising a lipophilic anchor, an electrophilic serine "trap", and an acidic binding moiety. The resulting 1,3-diheteroatom-substituted propan-2-ones were evaluated as inhibitors of cPLA(2) in both aggregated bilayer and soluble substrate assays. Systematic variation of the lipophilic, electrophilic, and acidic groups revealed a well-defined structure-activity relationship against the enzyme. Optimization of each group led to compound 22 (AR-C70484XX), which contains a decyloxy lipophilic side chain, a 1,3-diaryloxypropan-2-one moiety as a unique serine trap, and a benzoic acid as the acidic binding group. AR-C70484XX was found to be among the most potent in vitro inhibitors of cPLA(2) described to date being more than 20-fold more active against the isolated enzyme (IC(50) = 0.03 microM) than the standard cPLA(2) inhibitor, arachidonyl trifluoromethyl ketone (AACOCF(3)), and also greater than 10-fold more active than AACOCF(3) against the cellular production of arachidonic acid by HL60 cells (IC(50) = 2.8 microM).