ORGN 476 |
| Mila Du, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965 |
| TNF-a is a pro-inflammatory cytokine that is believed to play a role in the etiology of rheumatoid arthritis, Crohn’s disease and other disease states. TNF-a converting enzyme (TACE) is the enzyme predominantly responsible for the formation of soluble TNF-a through the cleavage of membrane-bound TNF-a. Computer modeling and x-ray crystallography of ligands in the enzyme active site revealed design opportunities for optimizing TACE inhibition. The resulting butynyloxy P1’ group has been found to be effective in a series of anthranilate-based hydroxamic acids for increasing potency against TACE in a cell-free assay, and in LPS-stimulated THP cells. The synthesis, in vitro and in vivo activity of a representative sample of butynyloxy P1’ derivatives of a series of heterocyclic amino acid TACE inhibitors is presented.
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Technical Achievement in Organic Chemistry Awards
8:30 AM-11:25 AM, Wednesday, September 10, 2003 Sheraton New York -- Imperial Ballroom A, Oral
Division of Organic Chemistry |