Chloroquine and Chloroquinoline Derivatives as Models for the Design of Modulators of Amyloid Peptide Precursor Metabolism

Patricia Melnyk (1) , Valérie Vingtdeux (1) , Stéphane Burlet , Sabiha Eddarkaoui (1) , Marie-Eve Grosjean (1) , Paul-Emmanuel Larchanché (1) , Guillaume Hochart (1) , Christian Sergheraert (2) , Cecilia Estrella , Mathieu Barrier , Virginie Poix , Pauline Plancq , Cécile Lannoo , Malika Hamdane (1) , André Delacourte (1) , Philippe Verwaerde , Luc Buee (1) , Nicolas Sergeant (1)

1 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837
2 Université de Lille, Droit et Santé

The amyloid precursor protein (APP) plays a central role in Alzheimer’s disease (AD). Preventing deregulated APP processing by inhibiting amyloidogenic processing of carboxy-terminal fragments (APP-CTFs), and reducing the toxic effect of amyloid beta (Aβ) peptides remain an effective therapeutic strategy. We report the design of piperazine-containing compounds derived from chloroquine structure and evaluation of their effects on APP metabolism and ability to modulate the processing of APP-CTF and the production of Aβ peptide. Compounds which retained alkaline properties and high affinity for acidic cell compartments were the most effective. The present study demonstrates that (1) the amino side chain of chloroquine can be efficiently substituted by a bis(alkylamino)piperazine chain, (2) the quinoline nucleus can be replaced by a benzyl or a benzimidazole moiety, and (3) pharmacomodulation of the chemical structure allows the redirection of APP metabolism toward a decrease of Aβ peptide release, and increased stability of APP-CTFs and amyloid intracellular fragment. Moreover, the benzimidazole compound 29 increases APP-CTFs in vivo and shows promising activity by the oral route. Together, this family of compounds retains a lysosomotropic activity which inhibits lysosome-related Aβ production, and is likely to be beneficial for therapeutic applications in AD.

Mots clés: Alzheimer’s disease; amyloid precursor protein; Chloroquine; piperazine

Domaines: Chimie thérapeutique; Neurobiologie

Patricia Melnyk, Valérie Vingtdeux, Stéphane Burlet, Sabiha Eddarkaoui, Marie-Eve Grosjean, et al.. Chloroquine and Chloroquinoline Derivatives as Models for the Design of Modulators of Amyloid Peptide Precursor Metabolism. ACS Chemical Neuroscience, 2015, 6 (4), pp.559-569. ⟨10.1021/cn5003013⟩. ⟨hal-02060814⟩