Neuropharmacology

QPS Austria Scientists Publish on Promising New, Multitarget Anti-Alzheimer’s Agent

Daniela Brunner, Nicole Taub and Birgit Hutter-Paier from QPS-Austria co-authored a paper on the high yield synthesis and efficacy of AVCRI104P4, a new anti-Alzheimer’s compound. This compound is a hybrid of donazepil - a reversible acetylcholinesterase inhibitor used to palliate mild to moderate Alzheimer's disease (AD)-type dementia - and huprine Y, a compound with a very high affinity for the active site of acetylcholinesterase. As such, the new agent exhibits a promising in vitro multitarget profile likely to be useful in the treatment of AD.

The key to the hybrid compound’s synthesisin quantity is the innovativeuse of chiral high-performance liquid chromotography (HPLC) to separate outintermediate racemic huprine Y.

When administered to certain transgenic nematode strains used as simplified animal models of AD,the new compound led to significant protection from the toxicity induced by Aβ42 peptides, precursors to AD amyloid plaques. However, this protective effect was not necessarily accompaniedby a reduction in amyloid deposits. Administration to an AD mouse model improved short-term memory but did not alter brain levels of Aβ peptides, nor cortical or hippocampal amyloid plaque load.

Despite the clear protective and cognitive effects of AVCRI104P4, the authors felt 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. The next step will thus be to focus on improving the compound’s anti-amyloid/anticholinesterase activity ratio.

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