TY - JOUR
T1 - Tertiary Amine Pyrazolones and Their Salts as Inhibitors of Mutant Superoxide Dismutase 1-Dependent Protein Aggregation for the Treatment of Amyotrophic Lateral Sclerosis
AU - Zhang, Yinan
AU - Zhao, Kevin Tianmeng
AU - Fox, Susan G.
AU - Kim, Jinho
AU - Kirsch, Donald R.
AU - Ferrante, Robert J.
AU - Morimoto, Richard I.
AU - Silverman, Richard B.
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/7/17
Y1 - 2015/7/17
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.5b00561
DO - 10.1021/acs.jmedchem.5b00561
M3 - Article
C2 - 26186011
AN - SCOPUS:84939135075
SN - 0022-2623
VL - 58
SP - 5942
EP - 5949
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 15
ER -