Bioorg Med Chem Lett. 2008 Feb 15;18(4):1288-92. Epub 2008 Jan 11.

Alpha,Beta-cyclic-beta-benzamido hydroxamic acids: Novel oxaspiro[4.4]nonane templates for the discovery of potent, selective, orally bioavailable inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).

Ott GR, Asakawa N, Liu RQ, Covington MB, Qian M, Vaddi K, Newton RC, Trzaskos JM, Christ DD, Galya L, Scholz T, Marshall W, Duan JJ.

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Departments of Discovery Chemistry and Discovery Biology, Bristol-Myers Squibb Research and Development, Rte 206 and Province Line Road, Princeton, NJ 08543, USA.

Abstract

Two novel oxaspiro[4.4]nonane beta-benzamido hydroxamic scaffolds have been synthesized in enantio- and diasteriomerically pure form. These templates proved to be exceptional platforms that have led to the discovery of potent inhibitors of TACE that are active in a cellular assay measuring suppression of LPS-induced TNF-alpha. Furthermore, these inhibitors are selective against related MMPs, demonstrate permeability in a Caco-2 assay, and display good oral bioavailability.

PMID:: 18234496; [PubMed - indexed for MEDLINE]

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