10.1021/jm2014277.s001
Tian Chen
Tian
Chen
Radhia Benmohamed
Radhia
Benmohamed
Jinho Kim
Jinho
Kim
Karen Smith
Karen
Smith
Daniel Amante
Daniel
Amante
Richard I. Morimoto
Richard I.
Morimoto
Donald
R. Kirsch
Donald
R.
Kirsch
Robert J. Ferrante
Robert J.
Ferrante
Richard B. Silverman
Richard B.
Silverman
ADME-Guided Design and
Synthesis of Aryloxanyl Pyrazolone
Derivatives To Block Mutant Superoxide Dismutase 1 (SOD1) Cytotoxicity
and Protein Aggregation: Potential Application for the Treatment of
Amyotrophic Lateral Sclerosis
American Chemical Society
2016
ALS mouse model
ether derivatives
analogue
mouse model
chemical modification
neurodegenerative disorder
Amyotrophic Lateral SclerosisAmyotrophic
pharmacokinetic profile
ADME properties
plasma stability
neurodegenerative disease
ASP scaffold
throughput screening assay
arylsulfanyl pyrazolone
Protein Aggregation
Block Mutant Superoxide Dismutase 1
ASP compounds
Aryloxanyl Pyrazolone Derivatives
vivo
SOD
pharmacokinetic properties
brain levels
Potential Application
aryloxanyl pyrazolone scaffold
brain penetration
potency
2016-02-22 08:52:35
Journal contribution
https://acs.figshare.com/articles/journal_contribution/ADME_Guided_Design_and_Synthesis_of_Aryloxanyl_Pyrazolone_Derivatives_To_Block_Mutant_Superoxide_Dismutase_1_SOD1_Cytotoxicity_and_Protein_Aggregation_Potential_Application_for_the_Treatment_of_Amyotrophic_Lateral_Sclerosis/2560963
Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative
disease currently without a cure. The arylsulfanyl pyrazolone (ASP)
scaffold was one of the active scaffolds identified in a cell-based
high throughput screening assay targeting mutant Cu/Zn superoxide
dismutase 1 (SOD1) induced toxicity and aggregation as a marker for
ALS. The initial ASP hit compounds were potent and had favorable ADME
properties but had poor microsomal and plasma stability. Here, we
identify the microsomal metabolite and describe synthesized analogues
of these ASP compounds to address the rapid metabolism. Both in vitro
potency and pharmacological properties of the ASP scaffold have been
dramatically improved via chemical modification to the corresponding
sulfone and ether derivatives. One of the ether analogues (<b>13</b>), with superior potency and in vitro pharmacokinetic properties,
was tested in vivo for its pharmacokinetic profile, brain penetration,
and efficacy in an ALS mouse model. The analogue showed sustained
blood and brain levels in vivo and significant activity in the mouse
model of ALS, thus validating the new aryloxanyl pyrazolone scaffold
as an important novel therapeutic lead for the treatment of this neurodegenerative
disorder.