We describe the multigram synthesis and in vivo efficacy studies of\na donepezilââ?¬â??huprine hybrid that has been found to display a promising in vitro multitarget\nprofile of interest for the treatment of Alzheimerââ?¬â?¢s disease (AD). Its synthesis features as\nthe key step a novel multigram preparative chromatographic resolution of intermediate\nracemic huprine Y by chiral HPLC. Administration of this compound to transgenic CL4176 and CL2006 Caenorhabditis elegans strains expressing human AÃ?²42, here used as\nsimplified animal models of AD, led to a significant protection from the toxicity induced\nby AÃ?²42. However, this protective effect was not accompanied, in CL2006 worms, by a\nreduction of amyloid deposits. Oral administration for 3 months to transgenic APPSL mice, a\nwell-established animal model of AD, improved short-term memory, but did not alter brain\nlevels of AÃ?² peptides nor cortical and hippocampal amyloid plaque load. Despite the clear\nprotective and cognitive effects of AVCRI104P4, the lack of AÃ?² lowering effect in vivo\nmight be related to its lower in vitro potency toward AÃ?² aggregation and formation as\ncompared with its higher anticholinesterase activities. Further lead optimization in this\nseries should thus focus on improving the anti-amyloid/anticholinesterase activity ratio.
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