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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Aranapakam V, Davis JM, Grosu GT, Baker J, Ellingboe J, Zask A, Levin JI, Sandanayaka VP, Du M, Skotnicki JS, DiJoseph JF, Sung A, Sharr MA, Killar LM, Walter T, Jin G, Cowling R, Tillett J, Zhao W, McDevitt J, Xu ZB

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.

J Med Chem. 2003 Jun 5;46(12):2376-96.

PubMed ID

12773042 [ View in PubMed

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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. In our preceding paper, we have reported on a series of novel and orally active N-hydroxy-alpha-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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
CTS-1027	Collagenase 3	IC 50 (nM)	2	N/A	N/A	Details