title: A chemical chaperone-based drug candidate is effective in a mouse model of amyotrophic lateral sclerosis (ALS).
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective death of motor neurons and skeletal muscle atrophy. The majority of ALS cases are acquired spontaneously, with inherited disease accounting for only 10 % of all cases. Recent studies provide compelling evidence that aggregates of misfolded proteins underlie both types of ALS. Small molecules such as artificial chaperones can prevent or even reverse the aggregation of proteins associated with various human diseases. However, their very high active concentration (micromolar range) severely limits their utility as drugs. We synthesized several ester and amide derivatives of chemical chaperones. The lead compound 14, 3-((5-((4,6-dimethylpyridin-2-yl)methoxy)-5-oxopentanoyl)oxy)-N,N-dimethylpropan-1-amine oxide shows, in the micromolar concentration range, both neuronal and astrocyte protective effects in vitro; at daily doses of 10 mg kg(-1) 14 improved the neurological functions and delayed body weight loss in ALS mice. Members of this new chemical chaperone derivative class are strong candidates for the development of new drugs for ALS patients.
authors.affiliation: Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, Ramat Gan, 529002 (Israel).
authors.forename: Tamar
authors.initials: T
authors.lastname: Getter
authors.forename: Ilana
authors.initials: I
authors.lastname: Zaks
authors.forename: Yael
authors.initials: Y
authors.lastname: Barhum
authors.forename: Tali
authors.initials: T
authors.lastname: Ben-Zur
authors.forename: Sebastian
authors.initials: S
authors.lastname: Böselt
authors.forename: Simpson
authors.initials: S
authors.lastname: Gregoire
authors.forename: Olga
authors.initials: O
authors.lastname: Viskind
authors.forename: Tom
authors.initials: T
authors.lastname: Shani
authors.forename: Hugo
authors.initials: H
authors.lastname: Gottlieb
authors.forename: Omer
authors.initials: O
authors.lastname: Green
authors.forename: Moran
authors.initials: M
authors.lastname: Shubely
authors.forename: Hanoch
authors.initials: H
authors.lastname: Senderowitz
authors.forename: Adrian
authors.initials: A
authors.lastname: Israelson
authors.forename: Inchan
authors.initials: I
authors.lastname: Kwon
authors.forename: Susanne
authors.initials: S
authors.lastname: Petri
authors.forename: Daniel
authors.initials: D
authors.lastname: Offen
authors.forename: Arie
authors.initials: A
authors.lastname: Gruzman
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure
chemical_list: D000577:Amides
keywords: amyotrophic lateral sclerosis; chemical chaperones; drug development; in vivo studies; superoxide dismutase 1