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 Aβ42, here used as simplified animal models of AD, led to a significant protection from the toxicity induced by Aβ42. 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 Aβ peptides nor cortical and hippocampal amyloid plaque load. Despite the clear protective and cognitive effects of AVCRI104P4, the lack of Aβ lowering effect in vivo might be related to its lower in vitro potency toward Aβ 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.
Highlights
Alzheimer’s disease (AD) currently constitutes a huge human tragedy due to its devastating effects on the quality of life of patients, and its increasingly higher prevalence and mortality
Because purification of AVCRI104P4 by standard silica gel column chromatography had been a quite difficult, low yield, and tedious task in the low scale synthesis [12], a quite attractive option for the scale-up synthesis might involve the direct preparative chiral chromatography of multigram amounts of the crude racemic final compound, inasmuch as separation of AVCRI104P4 from its enantiomer and from unreacted starting materials or other byproducts formed in the reaction might be done at once, thereby avoiding a previous achiral chromatographic step
These results indicate that the protective effect of AVCRI104P4 against Aβ toxicity was greater in CL4176 than in CL2006 nematodes, suggesting that this drug may exert its activity against the oligomeric assemblies of Aβ, without affecting amyloid plaque deposition and independently from its activities in the nanomolar (AChE) inhibitory activity
Summary
Alzheimer’s disease (AD) currently constitutes a huge human tragedy due to its devastating effects on the quality of life of patients, and its increasingly higher prevalence and mortality. A number of promising drug candidates have been developed in the past decade to separately hit one of the putative key players of AD neuropathogenesis, prominently the formation or the aggregation of the β-amyloid peptide (Aβ) [2,3] None of these single-target disease-modifying agents has demonstrated to be effective and safe in clinical trials, so far. We have recently developed a new structural family of hybrid compounds, which were designed by combination of pharmacophoric moieties of two potent inhibitors of acetylcholinesterase (AChE), namely donepezil and huprine Y [12] The rationale behind this design was to enable interactions at different sites of a particular target, simultaneously affecting two important targets in the context of AD treatment. The behavioural effects of AVCRI104P4 in APPSL transgenic mice orally treated for 3 months, as well as its effects on Aβ levels in cerebrospinal fluid (CSF) and brain homogenates, and on the amyloid load in cortex and hippocampus have been determined
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