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Arylsulfanyl pyrazolones block mutant SOD1-G93A aggregation. Potential application for the treatment of amyotrophic lateral sclerosis |
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| Authors: | Chen Tian Benmohamed Radhia Arvanites Anthony C Ralay Ranaivo Hantamalala Morimoto Richard I Ferrante Robert J Watterson D Martin Kirsch Donald R Silverman Richard B |
| Institution: | a Department of Chemistry, Northwestern University, Evanston, IL 60208-3113, USA b Cambria Pharmaceuticals, Cambridge, MA 02142, USA c Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208-3113, USA d Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208-3500, USA e Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA f Department of Neurology, Laboratory Medicine and Pathology, and Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA g Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208-3113, USA |
| 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 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. |
| Keywords: | Arylsulfanyl pyrazolone Amyotrophic lateral sclerosis Mutant G93A SOD1 Blood-brain barrier penetration |
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