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

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• 作者：Yinan Zhang ; Kevin Tianmeng Zhao ; Susan G. Fox ; Jinho Kim ; Donald R. Kirsch ; Robert J. Ferrante ; Richard I. Morimoto ; Richard B. Silverman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：58
• 期：15
• 页码：5942-5949
• 全文大小：361K
• ISSN：1520-4804

文摘

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鈥揳ctivity 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鈥揵rain barrier permeation. These results indicate that tertiary amine pyrazolones comprise a valuable class of ALS drug candidates.