Synthesis and Evaluation of 5-(Heteroarylmethylene)hydantoins as Glycogen Synthase Kinase-3β Inhibitors

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase which plays a center role in the phosphorylation of a wide variety of proteins, generally leading to their inactivation. As such, GSK-3 is viewed as a therapeutic target. An ever-increasing number of small organic molecule inhibitors of GSK-3 have been reported. Phenylmethylene hydantoins are known to exhibit a wide range of inhibitory activities including for GSK-3 beta. A family of fourteen 2-heterocycle substituted methylene hydantoins (14, 17-29) were prepared and evaluated for the inhibition of GSK-3 beta at 25 mu M. The IC50 values of five of these compounds was determined; the two best inhibitors are 5-[(4 '-chloro-2-pyridinyl)methylene]hydantoin (IC50 = 2.14 +/- 0.18 mu M) and 5-[(6 '-bromo-2-pyridinyl)methylene]hydantoin (IC50 = 3.39 +/- 0.16 mu M). The computational docking of the compounds with GSK-3 beta (pdb 1q41) revealed poses with hydrogen bonding to the backbone at Val135. The 5-[(heteroaryl)methylene]hydantoins did not strongly inhibit other metalloenzymes, demonstrating poor inhibitory activity against matrix metalloproteinase-12 at 25 mu M and against human carbonic anhydrase at 200 mu M, and were not inhibitors for Staphylococcus aureus pyruvate carboxylase at concentrations >1000 mu M.