title: Tertiary Amine Pyrazolones and Their Salts as Inhibitors of Mutant Superoxide Dismutase 1-Dependent Protein Aggregation for the Treatment of Amyotrophic Lateral Sclerosis.
abstract: Pyrazolone derivatives have previously been found to be inhibitors of Cu/Zn superoxide dismutase 1 (SOD1)-dependent protein aggregation, which extended survival of an amyotrophic lateral sclerosis (ALS) mouse model. On the basis of ADME analysis, we describe herein a new series of tertiary amine-containing pyrazolones and their structure-activity relationships. Further conversion to the conjugate salts greatly improved their solubility. Phosphate compound 17 exhibited numerous benefits both to cellular activity and to CNS-related drug-like properties in vitro and in vivo, including microsomal stability, tolerated toxicity, and blood-brain barrier permeation. These results indicate that tertiary amine pyrazolones comprise a valuable class of ALS drug candidates.
authors.affiliation: †Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208-3113, United States.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: †Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208-3113, United States.
authors.forename: Kevin Tianmeng
authors.initials: KT
authors.lastname: Zhao
authors.affiliation: ‡Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208-3500, United States.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Fox
authors.affiliation: §Neurological Surgery, Neurology, and Neurobiology Departments, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States.|∥Geriatric Research Educational and Clinical Center (00-GR-H), V.A. Pittsburgh Healthcare System, 7180 Highland Drive, Pittsburgh, Pennsylvania 15206, United States.
authors.forename: Jinho
authors.initials: J
authors.lastname: Kim
authors.affiliation: ⊥Cambria Pharmaceuticals, Cambridge, Massachusetts 02142, United States.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Kirsch
authors.affiliation: §Neurological Surgery, Neurology, and Neurobiology Departments, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States.|∥Geriatric Research Educational and Clinical Center (00-GR-H), V.A. Pittsburgh Healthcare System, 7180 Highland Drive, Pittsburgh, Pennsylvania 15206, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferrante
authors.affiliation: ‡Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208-3500, United States.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
authors.affiliation: †Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208-3113, United States.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000588:Amines / Q000737:chemistry; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D047069:Pyrazolones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D012492:Salts; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors*
chemical_list: D000588:Amines; D047069:Pyrazolones; D012492:Salts; D013482:Superoxide Dismutase