- Synthesis and structure - Activity relationship of N-substituted 4-arylsulfonylpiperidine-4-hydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis
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The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. In our preceding paper, we have reported on a series of novel and orally active N-hydroxy-α-phenylsulfonylacetamide derivatives. However, these compounds had two drawbacks (moderate selectivity and chirality issues). To circumvent these two problems, a series of novel and orally active N-substituted 4-benzenesulfonylpiperidine-4-carboxylic acid hydroxyamide derivatives have been synthesized. The present paper deals with the synthesis and SAR of these compounds. Among the several compounds synthesized, derivative 55 turned out to be a potent, selective, and an orally active MMP inhibitor in the clinically relevant advanced rabbit osteoarthritis model. Detailed pharmacokinetics and metabolism data are described.
- Aranapakam, Venkatesan,Davis, Jamie M.,Grosu, George T.,Baker, Jannie,Ellingboe, John,Zask, Arie,Levin, Jeremy I.,Sandanayaka, Vincent P.,Du, Mila,Skotnicki, Jerauld S.,DiJoseph, John F.,Sung, Amy,Sharr, Michele A.,Killar, Loran M.,Walter, Thomas,Jin, Guixian,Cowling, Rebecca,Tillett, Jeff,Zhao, Weiguang,McDevitt, Joseph,Xu, Zhang Bao
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p. 2376 - 2396
(2007/10/03)
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