A Chemical Chaperone-Based Drug Candidate is Effective in a Mouse Model of Amyotrophic Lateral Sclerosis (ALS)

• Published in: ChemMedChem 2015-05, Vol.10 (5), p.850-861
• Main Authors: Getter, Tamar, Zaks, Ilana, Barhum, Yael, Ben-Zur, Tali, Böselt, Sebastian, Gregoire, Simpson, Viskind, Olga, Shani, Tom, Gottlieb, Hugo, Green, Omer, Shubely, Moran, Senderowitz, Hanoch, Israelson, Adrian, Kwon, Inchan, Petri, Susanne, Offen, Daniel, Gruzman, Arie
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - therapeutic use; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - drug therapy; Animals; Cells, Cultured; chemical chaperones; Disease Models, Animal; Dose-Response Relationship, Drug; drug development; Humans; in vivo studies; Medical research; Mice; Mice, Transgenic; Molecular Structure; superoxide dismutase 1
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201500045

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. Low concentration efficacy: Compound 14 demonstrated biological effects in ALS mice, showing the prevention of body mass loss and improvements in neurological function. In vitro studies revealed that this lead compound significantly decreases the formation of misfolded mutated superoxide dismutase 1 (SOD1) and prevents ER‐stress‐induced apoptosis. In addition, 14 decreased the levels of known ER stress markers and decreased the formation of misfolded mutant SOD1 aggregates.