Potent, exceptionally selective, orally bioavailable inhibitors of TNF-α Converting Enzyme (TACE): Novel 2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamide P1′ substituents

Bristol-Myers Squibb, New York, New York, United States
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 04/2008; 18(5):1577-82. DOI: 10.1016/j.bmcl.2008.01.075
Source: PubMed


Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1' substituents in conjunction with unique constrained beta-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-alpha Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression of LPS-induced TNF-alpha in human whole blood and orally bioavailable. (c) 2008 Elsevier Ltd. All rights reserved.

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    • "Because of the clinical success of anti-TNF-a biological drugs such as etanercept (Enbrel), infliximab (Remicade) and adalimumab (Humira) more attention has driven to target TNF-a in RA therapy. One of the promising approaches to discovery of inhibitors of TNF-a is the inhibition of TACE (Chun et al., 2008; Park et al., 2009; Ott et al., 2008a, b). Efforts are taken to suppress the amount of circulating soluble TNF-a by designing orally active small molecule of TACE inhibitors. "
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