α,β-Cyclic-β-benzamido hydroxamic acids:: Novel oxaspiro[4.4] nonane templates for the discovery of potent, selective, orally bioavailable inhibitors of tumor necrosis factor-α converting enzyme (TACE)

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. (c) 2008 Elsevier Ltd. All rights reserved.