10.1021/jm2014277.s001 Tian Chen Tian Chen Radhia Benmohamed Radhia Benmohamed Jinho Kim Jinho Kim Karen Smith Karen Smith Daniel Amante Daniel Amante Richard I. Morimoto Richard I. Morimoto Donald R. Kirsch Donald R. Kirsch Robert J. Ferrante Robert J. Ferrante Richard B. Silverman Richard B. Silverman 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 American Chemical Society 2016 ALS mouse model ether derivatives analogue mouse model chemical modification neurodegenerative disorder Amyotrophic Lateral SclerosisAmyotrophic pharmacokinetic profile ADME properties plasma stability neurodegenerative disease ASP scaffold throughput screening assay arylsulfanyl pyrazolone Protein Aggregation Block Mutant Superoxide Dismutase 1 ASP compounds Aryloxanyl Pyrazolone Derivatives vivo SOD pharmacokinetic properties brain levels Potential Application aryloxanyl pyrazolone scaffold brain penetration potency 2016-02-22 08:52:35 Journal contribution https://acs.figshare.com/articles/journal_contribution/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/2560963 Amyotrophic 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 (<b>13</b>), 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.