RESUMEN
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.
Asunto(s)
Ácido 4-Aminobenzoico/síntesis química , Aminobenzoatos/síntesis química , Inhibidores Enzimáticos/síntesis química , Hipoglucemiantes/síntesis química , Fenilalanina/síntesis química , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , para-Aminobenzoatos , Ácido 4-Aminobenzoico/farmacocinética , Ácido 4-Aminobenzoico/farmacología , Administración Oral , Secuencia de Aminoácidos , Aminobenzoatos/farmacocinética , Aminobenzoatos/farmacología , Animales , Disponibilidad Biológica , Glucemia/análisis , Células CACO-2 , Dominio Catalítico , Cristalografía por Rayos X , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Permeabilidad , Fenilalanina/análogos & derivados , Fenilalanina/farmacocinética , Fenilalanina/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Proteínas Tirosina Fosfatasas/química , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
