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.
Zhang, Yinan,Zhao, Kevin Tianmeng,Fox, Susan G.,Kim, Jinho,Kirsch, Donald R.,Ferrante, Robert J.,Morimoto, Richard I.,Silverman, Richard B.
The present invention relates to new derivatives of the family of 3-arylpyrazoles of formula (I), their methods of preparation, the compositions containing them and their utilization for the protection of plants against fungal diseases. STR1
-
(2008/06/13)
More Articles about upstream products of 109346-95-4