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

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.

• Authors: Yinan Zhang, Kevin Tianmeng Zhao, Susan G Fox, Jinho Kim, Donald R Kirsch, Robert J Ferrante, Richard I Morimoto, Richard B Silverman
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 15 Pg. 5942-9 (Aug 13 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26186011 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Amines
• Pyrazolones
• Salts
• Superoxide Dismutase

Topics

• Amines (chemistry)
• Amyotrophic Lateral Sclerosis (drug therapy)
• Animals
• Female
• Humans
• In Vitro Techniques
• Male
• Mice
• Pyrazolones (chemistry, pharmacology, therapeutic use)
• Salts
• Structure-Activity Relationship
• Superoxide Dismutase (antagonists & inhibitors)