Potent,Selective Pyrone-Based Inhibitors of Stromelysin-1

摘要

This communication describes the design and synthesis of pyrone-based inhibitors of matrix metalloproteinases(MMPs)that show superior potency over their hydroxamate analogues.The zinc-(II)-dependent MMPs have been pursued as chemotherapeutic targets for the treatment of illnesses,such as cancer,arthritis,and heart disease.Consequently,over the past two decades,attempts to interfere with MMP activity have yielded numerous inhibitors.' MMP inhibitors(MPIs)are based on a two-part strategy:chelation of the catalytic zinc(II)ion combined with noncovalent interactions within "subsite" pockets in the MMP active site.