RESUMEN
A library of 1,3-disubstituted 2-propanols was synthesized and evaluated as low molecular weight probes for ß-secretase inhibition. By screening a library of 121 1,3-disubstituted 2-propanol derivatives, we identified few compounds inhibiting the enzyme at low micromolar concentrations. The initial hits were optimized to yield a potent BACE-1 inhibitor exhibiting an IC(50) constant in the nanomolar range. Exploration of the pharmacological properties revealed that these small molecular inhibitors possessed a high selectivity over cathepsin D and desirable physicochemical properties beneficial to cross the blood-brain barrier.
Asunto(s)
2-Propanol/síntesis química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , 2-Propanol/metabolismo , 2-Propanol/farmacología , Barrera Hematoencefálica/metabolismo , Catepsina D/antagonistas & inhibidores , Fenómenos Químicos , Estructura Molecular , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/farmacología , Relación Estructura-ActividadRESUMEN
Two fluorous diazirine photolabels were designed, synthesized and subjected to photoactivation studies. The photoactivation studies revealed an unexpected photoreaction when the fluorous tag was directly connected to the diazirine ring, leading to the formation of a fluorous alkene. The more efficient photolabel of the two was identified as a flexible precursor for target specific photoaffinity labels for fluorous proteomics by adding appropriate ligands depending on the target protein subset. As a proof of feasibility, mannose residues were added to the photolabel making it a potential photoaffinity label to tag proteins that bind mannose.