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.

Protein Homeostasis in Amyotrophic Lateral Sclerosis: Therapeutic Opportunities?

“…Pyrazolone-containing small molecules have been shown to block ALS mutant SOD1 mediated cytotoxicity and aggregation in a number of studies (Chen et al, 2012; Trippier et al, 2012; Zhang et al, 2013). The mechanism of action of pyrazolone was shown to be by activation of the proteasome, suggesting that proteasome activators may be of therapeutic benefit in ALS (Trippier et al, 2014).…”

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

“…In general, the potency of the tertiary amine pyrazolone analogues (Figure 3) is comparable to that of the arylazanylpyrazolone analogues. Detailed in our previous investigation of aryloxanylpyrazolones 19 and arylazanylpyrazolone, 20 the dichloro phenyl moiety was the most effective aromatic substitution pattern and was kept in the tertiary amine series. However, 3,5-dichloro-substitution in this series shows slightly better activity than the 2,4-dichloro-substitution in the arylazanylpyrazolones.…”

Morita–Baylis–Hillman adducts as building blocks of heterocycles: a simple approach to 4-substituted pyrazolones, and mechanism investigation via ESI–MS(/MS)

“…Among them, the pyrazolone core has been gaining increasing attention due to its applications, representing a versatile template for combinatorial and medicinal chemistry [2][3][4][5][6][7].…”