Synthesis and structure-activity relationship of alpha-sulfonylhydroxamic acids as novel,orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis |
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Authors: | Aranapakam Venkatesan Grosu George T Davis Jamie M Hu Baihua Ellingboe John Baker Jannie L Skotnicki Jerauld S Zask Arie DiJoseph John F Sung Amy Sharr Michele A Killar Loran M Walter Thomas Jin Guixian Cowling Rebecca |
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Affiliation: | Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. venkata@wyeth.com |
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Abstract: | 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. |
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