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

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 Aß42, here used as simplified animal models of AD, led to a significant protection from the toxicity induced by Aß42. 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 Aß peptides nor cortical and hippocampal amyloid plaque load. Despite the clear protective and cognitive effects of AVCRI104P4, the lack of Aß lowering effect in vivo might be related to its lower in vitro potency toward Aß 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.

Optimization of the chiral separation of a Ca-sensitizing drug on an immobilized polysaccharide-based chiral stationary phase: case study with a preparative perspective.

Sample solubility in the mobile phase and enantioselectivity are key factors in chiral preparative chromatography. In the search for a high throughput process for production of pure enantiomers, the rational design of the mobile phase and the selection of a suitable chiral stationary phase (CSP) are essential. However, one may sometimes be faced with the incompatibility between the CSP and the preferential eluent for sample solubility. Such a limitation may be circumvented by using an immobilized CSP such as CHIRALPAK IA. In this manuscript, the chiral separation of a Ca-sensitizing drug (EMD 53986) is optimized on CHIRALPAK IA in terms of sample solubility, enantioselectivity and preparative productivity. The approaches for method optimization and the impact of sample solubility on productivity are discussed. The preparative potential of CHIRALPAK IA is also demonstrated.