RESUMO
Protein Tyrosine phosphatase 1B (PTP1B) has been implicated as a key negative regulator of both insulin and leptin signaling pathways. Using an NMR-based screening approach with 15N- and 13C-labeled PTP1B, we have identified 2,3-dimethylphenyloxalylaminobenzoic acid (1) as a general, reversible, and competitive PTPase inhibitor. Structure-based approach guided by X-ray crystallography facilitated the development of 1 into a novel series of potent and selective PTP1B inhibitors occupying both the catalytic site and a portion of the noncatalytic, second phosphotyrosine binding site. Interestingly, oral biovailability has been observed in rats for some compounds. Furthermore, we demonstrated in vivo plasma glucose lowering effects with compound 12d in ob/ob mice.
Assuntos
Ácido 4-Aminobenzoico/síntese química , Aminobenzoatos/síntese química , Inibidores Enzimáticos/síntese química , Hipoglicemiantes/síntese química , Fenilalanina/síntese química , Proteínas Tirosina Fosfatases/antagonistas & inibidores , para-Aminobenzoatos , Ácido 4-Aminobenzoico/farmacocinética , Ácido 4-Aminobenzoico/farmacologia , Administração Oral , Sequência de Aminoácidos , Aminobenzoatos/farmacocinética , Aminobenzoatos/farmacologia , Animais , Disponibilidade Biológica , Glicemia/análise , Células CACO-2 , Domínio Catalítico , Cristalografia por Raios X , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Permeabilidade , Fenilalanina/análogos & derivados , Fenilalanina/farmacocinética , Fenilalanina/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteínas Tirosina Fosfatases/química , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A salicylate second site binder was linked to three classes of phosphotyrosine mimetics to produce potent protein tyrosine phosphatase 1B (PTP1B) inhibitors which exhibit significant selectivity against other phosphatases including the most homologous member, TCPTP.
Assuntos
Inibidores Enzimáticos/química , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Proteínas Tirosina Fosfatases/química , Inibidores Enzimáticos/farmacologia , Humanos , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteínas Tirosina Fosfatases/metabolismo , Relação Estrutura-AtividadeRESUMO
We have previously reported a novel series of oxalyl-aryl-amino benzoic acid-based, catalytic site-directed, competitive, reversible protein tyrosine phosphatase 1B (PTP1B) inhibitors. With readily access to key intermediates, we utilized a solution phase parallel synthesis approach and rapidly identified a highly potent PTP1B inhibitor (19, K(i)=76 nM) with moderate selectivity (5-fold) over T-cell PTPase (TCPTP) through interacting with a second phosphotyrosine binding site (site 2) in the close proximity to the catalytic site.