Arylsulfanyl Pyrazolones Block Mutant SOD1-G93A Aggregation. Potential Application for the Treatment of Amyotrophic Lateral Sclerosis

摘要

Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure. Mutations in copper/zinc superoxide dismutase >1 (SOD1) have been implicated in the pathophysiology of this disease. Using a high-throughput screening assay expressing mutant G93A SOD1, two bioactive chemical hit compounds (>1 and >2), identified as arylsulfanyl pyrazolones, were identified. The structural optimization of this scaffold led to the generation of a more potent analogue (>19) with an EC50 of 170 nM. To determine the suitability of this class of compounds for further optimization, >1 was subjected to a battery of pharmacokinetic assays; most of the properties of >1 were good for a screening hit, except it had a relatively rapid clearance and short microsomal half-life stability. Compound >2 was found to be blood-brain barrier penetrating with a brain/plasma ratio = 0.19. The optimization of this class of compounds could produce novel therapeutic candidates for ALS patients.