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

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.