Tertiary Amine Pyrazolones and Their Salts as Inhibitors of Mutant Superoxide Dismutase 1-Dependent Protein Aggregation for the Treatment of Amyotrophic Lateral Sclerosis

Yinan Zhang, Kevin Tianmeng Zhao, Susan G. Fox, Jinho Kim, Donald R. Kirsch, Robert J. Ferrante, Richard I. Morimoto, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5942-5949
Number of pages8
JournalJournal of Medicinal Chemistry
Volume58
Issue number15
DOIs
StatePublished - Jul 17 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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