title: Arylsulfanyl pyrazolones block mutant SOD1-G93A aggregation. Potential application for the treatment of amyotrophic lateral sclerosis.
abstract: 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 EC(50) of 170nM. 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.
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, IL 60208-3113, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Chen
authors.forename: Radhia
authors.initials: R
authors.lastname: Benmohamed
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Arvanites
authors.forename: Hantamalala
authors.initials: H
authors.lastname: Ralay Ranaivo
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferrante
authors.forename: D Martin
authors.initials: DM
authors.lastname: Watterson
authors.forename: Donald R
authors.initials: DR
authors.lastname: Kirsch
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D047069:Pyrazolones / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D047069:Pyrazolones; D013482:Superoxide Dismutase