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ADME-Guided Design and Synthesis of Aryloxanyl Pyrazolone Derivatives To Block Mutant Superoxide Dismutase 1 (SOD1) Cytotoxicity and Protein Aggregation: Potential Application for the Treatment of Amyotrophic Lateral Sclerosis
journal contribution
posted on 2016-02-22, 08:52 authored by Tian Chen, Radhia Benmohamed, Jinho Kim, Karen Smith, Daniel Amante, Richard I. Morimoto, Donald
R. Kirsch, Robert J. Ferrante, Richard B. SilvermanAmyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative
disease currently without a cure. The arylsulfanyl pyrazolone (ASP)
scaffold was one of the active scaffolds identified in a cell-based
high throughput screening assay targeting mutant Cu/Zn superoxide
dismutase 1 (SOD1) induced toxicity and aggregation as a marker for
ALS. The initial ASP hit compounds were potent and had favorable ADME
properties but had poor microsomal and plasma stability. Here, we
identify the microsomal metabolite and describe synthesized analogues
of these ASP compounds to address the rapid metabolism. Both in vitro
potency and pharmacological properties of the ASP scaffold have been
dramatically improved via chemical modification to the corresponding
sulfone and ether derivatives. One of the ether analogues (13), with superior potency and in vitro pharmacokinetic properties,
was tested in vivo for its pharmacokinetic profile, brain penetration,
and efficacy in an ALS mouse model. The analogue showed sustained
blood and brain levels in vivo and significant activity in the mouse
model of ALS, thus validating the new aryloxanyl pyrazolone scaffold
as an important novel therapeutic lead for the treatment of this neurodegenerative
disorder.
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ALS mouse modelether derivativesanaloguemouse modelchemical modificationneurodegenerative disorderAmyotrophic Lateral SclerosisAmyotrophicpharmacokinetic profileADME propertiesplasma stabilityneurodegenerative diseaseASP scaffoldthroughput screening assayarylsulfanyl pyrazoloneProtein AggregationBlock Mutant Superoxide Dismutase 1ASP compoundsAryloxanyl Pyrazolone DerivativesvivoSODpharmacokinetic propertiesbrain levelsPotential Applicationaryloxanyl pyrazolone scaffoldbrain penetrationpotency
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