4-Acylamino-6-arylfuro[2,3- d]pyrimidines: potent and selective glycogen synthase kinase-3 inhibitors

A novel and potent series of selective GSK-3 inhibitors are described. Some derivatives showed excellent potency in a cellular assay. Modeling studies of a furo[2,3- d]pyrimidine GSK-3 hit compound 1 superimposed onto the X-ray crystal structure of a legacy pyrazolo[3,4- c]pyridazine GSK-3 inhibitor 2 led to the identification of 4-acylamino-6-arylfuro[2,3- d]pyrimidine template 3. Synthesis of analogues based on template 3 has resulted in a number of potent and selective GSK-3β inhibitors. The most potent and selective compound was the m-pyridyl analogue 24.