Journal of Medicinal Chemistry p. 5942 - 5949 (2015)
Update date:2022-08-29
Topics:
Zhang, Yinan
Zhao, Kevin Tianmeng
Fox, Susan G.
Kim, Jinho
Kirsch, Donald R.
Ferrante, Robert J.
Morimoto, Richard I.
Silverman, Richard B.
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.
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