Multi-Active Ligands for Alzheimer's Disease – MALAD

In order to reach this ambitious goal we decided to target one of the subtype of the serotonergic receptor (5-HT4R), which once activated could limit the amyloid pathology. This first activity will be associated with a second one targeting this time acetylcholinesterase, which is the therapeutic target of most of the drugs today on the market. In order to obtain such pleiotropic ligands a pharmacochemistry program has been engaged and the in vitro affinity of the ligands assessed towards the two targets. Further their drugability parameters (solubility, permeation, stability...) have been tested in order to select the most appropriate candidates for in vivo evaluation.

Among the numerous scientific results of this research program, one of the most representative is the identification of the promising properties of donecopride which has been presented in several media. This promising drug candidate appeared in several animal models to improve the memory performances and to limit the amyloïd pathology. Based on these promising properties, this family of compounds was patented by the university of Caen and the preclinical evaluation is currently ongoing.

The ANR project MALAD ANR-12-JS07-0012-01 which deal with the the development of pleiotropic ligands for Alzheimer's disease treatment was led by Pr Christophe Rochais. It was initiated in January 2013 in the Centre d'Etudes et de Recherche sur le Médicament de Normandie of the Université de Caen. This 42 months long project received an ANR funding of 181,000€ for a total cost of 253,000€.

A patent application was registered concerning our discovery in 2014, which is currently extended to several countries worldwide. Scientific results were also published for the first time in the journal of the Academy of Sciences of the United States of America (PNAS) in an article that has been widely followed. A numbers of publications, conferences and poster have also been presented by all the members of the research consortium

Because the pathogenesis of AD is complicated and related to the abnormality and dysfunction of multisystems, there has been no ideal drug for preventing and treating AD till now. The goal of current treatments is to improve neuronal dysfunction and produce only symptomatic benefits and drugs that act on the acetylcholine (ACh)-mediated system have been favored. It seems however necessary today to complete this symptomatic approach with a more disease-modifying one. In order to reach such a goal, it appears necessary to target one or several molecular causes implied in the pathogenesis of the disease. The aim of this project is to conceive and synthesize chemical compounds with adequate physicochemical properties and suitable in vitro profile to exert multiple activities of interest in the pathogenesis of AD. We have chosen among these causes the formation of senile plaques by aggregation of beta-amyloïd protein (AB) as a fundamental activity. In a first part of the project we want to develop, in order to prevent AB aggregation, agents liable to promote the cleavage of the APP by a-secretase allowing then the release of soluble and not amyloidogenic sAPPa. This effect can be obtained with serotonin 5-HT4 receptor (5-HT4R) agonists which are able to increase in vitro the extracellular release of sAPPa? decrease AB secretion in primary neurons and restore in vivo memory deficit in rat. Our goal will be to add to this first activity another manner to impact the amyloid aggregation in inhibiting the peripheric anionic site (PAS) of acetylcholinesterase (AChE), for which it has been shown that it forms a stable complex with BA favouring its aggregation into senile plaques. In a second part our program will focus on the development of multipotent agents which could exert direct AB aggregation and tau hyperphosphorylation inhibitory activities, in order to develop unique chemical structures which could be active on the two main molecular causes of AD. We propose, on the basis of our experience to produce such original Multi-Target-Directed Ligands with optimized physicochemical properties.