Reverse hydroxamate derivatives as metalloprotease inhibitors

Abstract

A series of reverse hydroxamate peptides are claimed as inhibitors of TNF-α convertase enzyme (TACE) and matrix metalloproteinases (MMPs). Syntheses are described for nineteen reverse hydroxamates. In vitro IC₅₀ values for inhibition of MMP-1, 3, 9, 13, TACE and cell-based TNF-α release are given for all nineteen examples. Most of the compounds exhibit broad spectrum MMP inhibition and are potent (< 100 nM) against TACE. One example of a TACE-selective compound is given. In vivo data for inhibition of serum TNF-α in a murine lipopolysaccharide (LPS) challenge model is also presented. MMP and TACE inhibitors may be useful for the treatment of chronic diseases such as cancer, arthritis and diabetes.

• arthritis
• matrix metalloproteinase (MMP)
• reverse hydroxamate
• TNF-α converting enzyme (TACE)