β-Aryl-Succinic Acid Hydroxamates as Dual Inhibitors of Matrix Metalloproteinases and Tumor Necrosis Factor Alpha Converting Enzyme

Novel hydroxamate inhibitors of tumor necrosis factor converting enzyme (TACE) and matrix metalloproteases (MMPs) have been synthesized via the Claisen−Ireland rearrangement. Aryl residues have been introduced to fill the enzyme's P1‘ specificity pocket. The best compound inhibits MMPs and TACE with nanomolar potency and inhibits the release of TNFα from cells with an IC₅₀ of 48 nM. Oral administration to rats inhibits the LPS-induced plasma TNFα levels with an ED₅₀ of 1 mg/kg.