Yinan Zhang1, Kevin Tianmeng Zhao1, Susan G Fox2, Jinho Kim3,4, Donald R Kirsch5, Robert J Ferrante3,4, Richard I Morimoto2, Richard B Silverman1. 1. †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. 2. ‡Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208-3500, United States. 3. §Neurological Surgery, Neurology, and Neurobiology Departments, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States. 4. ∥Geriatric Research Educational and Clinical Center (00-GR-H), V.A. Pittsburgh Healthcare System, 7180 Highland Drive, Pittsburgh, Pennsylvania 15206, United States. 5. ⊥Cambria Pharmaceuticals, Cambridge, Massachusetts 02142, United States.
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.
Pyrazolone derivatives have previously been found to be inhibitors of Cu/Zn n>an class="Gene">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.
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