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.

Abstract

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 (13), 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.

• Authors: Tian Chen, Radhia Benmohamed, Jinho Kim, Karen Smith, Daniel Amante, Richard I Morimoto, Donald R Kirsch, Robert J Ferrante, Richard B Silverman
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 1 Pg. 515-27 (Jan 12 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22191331 (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

• 5-((3,5-dichlorophenoxy)methyl)-1H-pyrazol-3(2H)-one
• Cytochrome P-450 Enzyme Inhibitors
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels
• Ethers
• Pyrazoles
• Pyrazolones
• SOD1 protein, human
• Sulfones
• Sod1 protein, mouse
• Sod1 protein, rat
• Superoxide Dismutase
• Superoxide Dismutase-1

Topics

• Amyotrophic Lateral Sclerosis (drug therapy)
• Animals
• Blood-Brain Barrier (metabolism)
• Caco-2 Cells
• Cell Membrane Permeability
• Cytochrome P-450 Enzyme Inhibitors
• Drug Design
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels (antagonists & inhibitors)
• Ethers (chemical synthesis, pharmacokinetics, pharmacology)
• HEK293 Cells
• Humans
• In Vitro Techniques
• Mice
• Microsomes, Liver (metabolism)
• Mutation
• Neurons (cytology, drug effects)
• Pyrazoles (chemical synthesis, pharmacokinetics, pharmacology)
• Pyrazolones (chemical synthesis, pharmacokinetics, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Solubility
• Structure-Activity Relationship
• Sulfones (chemical synthesis, pharmacokinetics, pharmacology)
• Superoxide Dismutase (antagonists & inhibitors, genetics)
• Superoxide Dismutase-1