Probing the physicochemical and structural requirements for glycogen synthase kinase-3α inhibition: 2D-QSAR for 3-anilino-4-phenylmaleimides

Glycogen synthase kinase-3α (GSK-3α) was recently found to be an attractive target for the treatment of Alzheimer’s disease due to its dual action in the formation of both amyloid plaques and neurofibrillary tangles. It is also a viable target for many other diseases, such as type 2 diabetes. Reported herein is a 2D-QSAR exploration of the physicochemical (hydrophobic, electronic, and steric) and structural requirements among 3-anilino-4-phenylmaleimides toward GSK-3α binding. Using Fujita–Ban and Hansch QSAR analysis, electronic and steric interactions at the 4-phenyl ring and hydrophobic interactions at the 3-anilino ring are shown to be crucial. Analysis of the 4-phenyl ring of these compounds using common aromatic substituent constants showed electron-withdrawing and bulky ortho substituents as imperative for GSK-3α inhibition.

GSK-3 is a potential target for the treatment of Alzheimer’s disease, type 2 diabetes, cancer, stroke, bipolar disorder and malaria. A recent study showed that inhibiting the α isoform is most promising in the treatment of Alzheimer’s disease. We have prepared a series of robust, systematic, quantitative structure–activity relationship models analyzing important features of GSK-3α inhibition by maleimides.Figure optionsDownload as PowerPoint slide