Arylsulfanyl Pyrazolones Block Mutant SOD1 Aggregation and have Potential Application for the Treatment of Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure. Active compounds that can be starting points for pursuing potential therapeutics were identified in a cell-based high throughput screening assay targeting ALS. One of the scaffolds assembled from the active hits was the arylsulfanyl pyrazolone (ASP) scaffold. Both potency and bioavailability of the ASP scaffold have been extensively improved via chemical modification. Original ASP hit compounds were determined to have poor metabolic/plasma stability, so the direct metabolite was identified. We subsequently synthesized ASP analogs that resolved this rapid metabolism problem. One of the ASP analogues with superior potency and predicted pharmacological properties was tested in vivo for pharmacokinetics and brain penetration and subsequently in an animal model of ALS. The analog showed sustained blood and brain levels in vivo and statistically significant activity in the mouse model of ALS, thus validating the scaffold as a therapeutic lead.