Synthesis and biological activity of flurbiprofen analogues as selective inhibitors of beta-amyloid 1-42 secretion
The study screened a library of NSAID flurbiprofen mimics to find selective inhibitors of Aβ secretion. Epidemiological studies have documented a reduced prevalence of AD among patients using NSAIDs. Despite these encouraging findings, all large, long-term, placebo controlled clinical trials aimed at reducing inflammation in the brain of AD patients have produced negative results. More recently, it has been shown that some NSAIDs decrease the production of Aβ42 in vitro and in vivo and counteract the progression of Aβ42 pathology in transgenic mouse models of AD. The proposed mechanism for this activity is an allosteric modulation of PS-1, the major component of the γ-secretase complex, the enzyme responsible for the formation of Aβ. The inhibition of Aβ42 production is independent of the anti-cyclooxygenase activity and is related to the chemical structure of the compounds. Unfortunately, the generic use of NSAIDs in AD is hampered by a significant gastrointestinal toxicity associated with COX inhibition. This study tried to identify new NSAIDs analogues endowed with potent and selective Aβ42 lowering activity but devoid of COX inhibitory activity, thus suitable for chronic use in AD patients. Appropriate substitution patterns at the alpha position of flurbiprofen allowed for the complete removal of anti-COX activity, while modifications at the terminal phenyl ring resulted in increased inhibitory potency onAβ42 secretion. In rats, some of the compounds appeared to be well absorbed after oral administration and to penetrate into the central nervous system. Studies in a transgenic mice model of AD showed that selected compounds significantly decreased plasma Aβ42 concentrations. These new flurbiprofen analogues represent potential drug candidates to be developed for the treatment of AD.
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