Novel TACE inhibitors in drug discovery: a review of patented compounds

Abstract

TNF-alpha converting enzyme (TACE), a pro-inflammatory cytokine, catalyzes the formation of TNF-alpha from membrane bound TNF-alpha precursor protein. TNF-alpha is believed to play pathophysiological roles in inflammation, anorexia, cachexia, septic shock, viral replication and so on. TNF-alpha is a key player in inflammation and joint damage in rheumatoid arthritis. While a variety of TACE inhibitors have been reported in the literature, a vast majority of these compounds are peptidic and peptide-like compounds that are expected to have bioavailability and pharmacokinetic problems, common to such compounds, limiting their clinical effectiveness. Low molecular mass, long acting, orally bioavailable inhibitors of TACE are, therefore, highly desirable for the treatment of potential chronic diseases mentioned above. A review of patented compounds as TACE inhibitors in drug discovery is given. A selection of interesting patents recorded from 2001 to 2009 is presented. Various novel TACE inhibitors developed by different companies have been discussed.