Synthesis and evaluation of novel heterocyclic inhibitors of GSK-3

Novel heterocyclic GSK-3 inhibitors based on a previously described template have been synthesized as a potential treatment for diabetes. Several compounds exhibited excellent potency which could be rationalized using ab initio calculations. A set of novel heterocyclic pyrimidyl hydrazones has been synthesized as inhibitors of glycogen synthase kinase-3 (GSK-3) with the most active exhibiting low nanomolar activity. Quantum mechanical calculations indicate that of the conformational factors that could determine binding affinity, the planarity of the phenyl ring in relation to the central core and the conformation of the hydrazone chain may be the most influential.