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