Synthesis and biological evaluation of glycogen synthase kinase 3 (GSK-3) inhibitors: an fast and atom efficient access to 1-aryl-3-benzylureas.

Abstract The glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes and has been linked to the pathogenesis of Alzheimer’s disease (AD). In the course of our research topic we synthesized a library of potent GSK-3 inhibitors. We utilized the urea scaffold present in the potent and highly selective GSK-3 inhibitor AR-A014418 (AstraZeneca). This moiety suits both (a) a convergent approach utilizing readily accessible building blocks and (b) a divergent approach based on a microwave heating assisted Suzuki coupling. We established a chromatography-free purification method to generate products with sufficient purity for the biological assays. The structure–activity relationship of the library provided the rationale for the synthesis of the benzothiazolylurea 66 (IC 50  = 140 nM) and the pyridylurea 62 (IC 50  = 98 nM), which displayed two to threefold enhanced activity versus the reference compound 18 (AR-A014418: IC 50  = 330 nM) in our assays.