J Med Chem 2003 Jun 5;46(12):2361-75
Aranapakam V, Grosu GT, Davis JM, Hu B, Ellingboe J, Baker JL, Skotnicki JS, Zask A, DiJoseph JF, Sung A, Sharr MA, Killar LM, Walter T, Jin G, Cowling R.
Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, and Wyeth Research, P.O. Box CN-8000, Princeton, New Jersey 08543.
The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation.
These enzymes are strictly regulated by endogenous inhibitors such as tissue inhibitors of MMPs and alpha(2)-macroglobulins.
Overexpression of these enzymes has been implicated in various pathological disorders such as arthritis, tumor metastasis, cardiovascular diseases, and multiple sclerosis.
Developing effective small-molecule inhibitors to modulate MMP activity is one approach to treat these degenerative diseases.
The present work focuses on the discovery and SAR of novel N-hydroxy-alpha-phenylsulfonylacetamide derivatives, which are potent, selective, and orally active MMP inhibitors.