title: Chloroquine and chloroquinoline derivatives as models for the design of modulators of amyloid Peptide precursor metabolism.
abstract: 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.
authors.affiliation: †Université de Lille, F-59000 Lille, France.|‡UDSL, EA 4481, UFR Pharmacie, F-59000 Lille, France.|§CNRS UMR8161, F-59000 Lille, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Melnyk
authors.affiliation: †Université de Lille, F-59000 Lille, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Vingtdeux
authors.affiliation: ⊥AlzProtect, F-59120 Loos, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Burlet
authors.affiliation: †Université de Lille, F-59000 Lille, France.
authors.forename: Sabiha
authors.initials: S
authors.lastname: Eddarkaoui
authors.affiliation: †Université de Lille, F-59000 Lille, France.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Grosjean
authors.affiliation: †Université de Lille, F-59000 Lille, France.|‡UDSL, EA 4481, UFR Pharmacie, F-59000 Lille, France.
authors.forename: Paul-Emmanuel
authors.initials: PE
authors.lastname: Larchanché
authors.affiliation: †Université de Lille, F-59000 Lille, France.|‡UDSL, EA 4481, UFR Pharmacie, F-59000 Lille, France.|§CNRS UMR8161, F-59000 Lille, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Hochart
authors.affiliation: †Université de Lille, F-59000 Lille, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Sergheraert
authors.affiliation: ⊥AlzProtect, F-59120 Loos, France.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Estrella
authors.affiliation: ⊥AlzProtect, F-59120 Loos, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Barrier
authors.affiliation: ⊥AlzProtect, F-59120 Loos, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Poix
authors.affiliation: ⊥AlzProtect, F-59120 Loos, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Plancq
authors.affiliation: ⊥AlzProtect, F-59120 Loos, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Lannoo
authors.affiliation: †Université de Lille, F-59000 Lille, France.
authors.forename: Malika
authors.initials: M
authors.lastname: Hamdane
authors.affiliation: †Université de Lille, F-59000 Lille, France.
authors.forename: André
authors.initials: A
authors.lastname: Delacourte
authors.affiliation: ⊥AlzProtect, F-59120 Loos, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Verwaerde
authors.affiliation: †Université de Lille, F-59000 Lille, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.affiliation: †Université de Lille, F-59000 Lille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sergeant
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology; D014867:Water / Q000737:chemistry
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011804:Quinolines; C078639:amyloid beta-protein (1-38); C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D014867:Water; D002738:Chloroquine
keywords: Alzheimer’s disease; Chloroquine; amyloid precursor protein; piperazine