Discovery of novel hydroxamates as highly potent tumor necrosis factor-α converting enzyme inhibitors. Part II: Optimization of the S3′ pocket

A series of cyclopropyl hydroxamic acids were prepared. Many of the compounds displayed picomolar affinity for the TACE enzyme while maintaining good to excellent selectivity profiles versus MMP-1, -2, -3, -7, -14, and ADAM-10. X-ray analysis of an inhibitor in the TACE active site indicated that the molecules bound to the enzyme in the S1′–S3′ pocket.

Graphical abstractWe herein disclose a novel series of cyclopropyl hydroxamates that are potent and selective TACE inhibitors with Ki values in the picomolar range.Figure optionsDownload full-size imageDownload as PowerPoint slide