Multigram synthesis and in vivo efficacy studies of a novel multitarget anti-Alzheimer's compound.

ABSTRACT: We describe the multigram synthesis and in vivo efficacy studies of a donepezil?huprine hybrid that has been found to display a promising in vitro multitarget profile of interest for the treatment of Alzheimer's disease (AD). Its synthesis features as the key step a novel multigram preparative chromatographic resolution of intermediate racemic huprine Y by chiral HPLC. Administration of this compound to transgenic CL4176 and CL2006 Caenorhabditis elegans strains expressing human A?42, here used as simplified animal models of AD, led to a significant protection from the toxicity induced by A?42. However, this protective effect was not accompanied, in CL2006 worms, by a reduction of amyloid deposits. Oral administration for 3 months to transgenic APPSL mice, a well-established animal model of AD, improved short-term memory, but did not alter brain levels of A? peptides nor cortical and hippocampal amyloid plaque load. Despite the clear protective and cognitive effects of AVCRI104P4, the lack of A? lowering effect in vivo might be related to its lower in vitro potency toward A? aggregation and formation as compared with its higher anticholinesterase activities. Further lead optimization in this series should thus focus on improving the anti-amyloid/anticholinesterase activity ratio.

SUBMITTER: Sola I 

PROVIDER: S-EPMC6272704 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature