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).
Bioorganic & medicinal chemistry letters 2008 Jan 11; In press
Ott G GR, Asakawa N N, Liu R RQ, Covington M MB, Qian M M, Vaddi K K, Newton R RC, Trzaskos J JM, Christ D DD, Galya L L, Scholz T T, Marshall W W, Duan J 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.
Keywords: TACE