Synthesis and Structure−Activity Relationships of 4-alkynyloxy Phenyl Sulfanyl, Sulfinyl, and Sulfonyl Alkyl Hydroxamates as Tumor Necrosis Factor-α Converting Enzyme and Matrix Metalloproteinase Inhibitors

A series of 4-alkynyloxy phenyl sulfanyl, sulfinyl and sulfony alkyl and piperidine-4-carboxylic acid hydroxamides were synthesized. Their structure−activity relationships, against tumor necrosis factor-α (TACE) and matrix metalloproteinase (MMP) inhibitor activities, are presented by investigating the oxidation state on sulfur and altering the P1‘ substituent. The sulfonyl derivatives 20−24 carrying a 4-butynyloxy moiety were selective TACE inhibitors over the MMPs tested. The sulfinyl derivatives showed a preference for a specific oxidation on sulfur as in compounds 25−28. The selectivity over MMPs was also demonstrated in the sulfonyl series. The enhanced cellular activity was achieved upon incorporating a butynyloxy substituent in the piperidene series. Compounds 64 and 65 were potent inhibitors of TNF-α release in the mouse at 100 mg/kg po.