Discovery of Novel Hydroxamates as Highly Potent Tumor Necrosis Factor-α Converting Enzyme Inhibitors: Part IDiscovery of Two Binding Modes

Through a de novo design approach, hydroxamates derived from trans-cyclopropyl dicarboxylate were examined as potential TNF-α converting enzyme (TACE) inhibitors. Two distinctive series of inhibitors (A and B) were identified and shown to have different structure−activity relationship trends and selectivity profiles against other matrix metalloproteases despite their close structural similarities. X-ray crystallography of the inhibitors binding to the TACE enzyme demonstrates that each series derives its activity from the opposite enantiomer of the cyclopropyl scaffolds, which display almost superimposable hydroxamate groups that coordinate to the zinc at the catalytic site. Mode A inhibitors occupy the S1′−S3′ binding pockets, whereas mode B resides in the nonprime binding sites.