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) |
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| Authors: | Ott Gregory R Asakawa Naoyuki Liu Rui-Qin Covington Maryanne B Qian Mingxin Vaddi Krishna Newton Robert C Trzaskos James M Christ David D Galya Laurine Scholz Thomas Marshall Will Duan James J-W |
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| Affiliation: | Departments of Discovery Chemistry and Discovery Biology, Bristol-Myers Squibb Research and Development, Rte 206 and Province Line Road, Princeton, NJ 08543, USA. |
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| 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. |
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