Synthesis and structure - Activity relationship of α-sulfonylhydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis

Venkatesan Aranapakam, George T. Grosu, Jamie M. Davis, Baihua Hu, John Ellingboe, Jannie L. Baker, Jerauld S. Skotnicki, Arie Zask, John F. DiJoseph, Amy Sung, Michele A. Sharr, Loran M. Killar, Thomas Walter, Guixian Jin, Rebecca Cowling

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

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 α2-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-α-phenylsulfonylacetamide derivatives, which are potent, selective, and orally active MMP inhibitors.

Original languageEnglish
Pages (from-to)2361-2375
Number of pages15
JournalJournal of Medicinal Chemistry
Volume46
Issue number12
DOIs
StatePublished - Jun 5 2003
Externally publishedYes

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