Optimization of Vinyl Sulfone Derivatives as Potent Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators for Parkinson’s Disease Therapy

Abstract

We previously developed a novel series of vinyl sulfones as nuclear factor erythroid 2-related factor 2 (Nrf2) activators with therapeutic potential for Parkinson’s disease (PD). However, the previously developed lead compound (1) exhibited undesirable druglike properties. Here, we optimized vinyl sulfones by introducing nitrogen heterocycles to improve druglike properties. Among the synthesized compounds, 17e was the most promising drug candidate with good druglike properties. Compound 17e showed superior effects on Nrf2 activation in cell-based assays compared to compound 1 (17e: half-maximal effective concentration (EC50) = 346 nM; 1: EC50 = 530 nM). Compound 17e was further confirmed to induce expression of Nrf2-dependent antioxidant enzymes at both mRNA and protein levels. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD, 17e significantly attenuated loss of tyrosine hydroxylase-immunopositive dopaminergic neurons, suppressed microglial activation, and alleviated PD-associated motor dysfunction. Thus, 17e is a novel Nrf2 activator with excellent druglike properties and represents a potential therapeutic candidate for PD.

Recovery of Depleted miR-146a in ALS Cortical Astrocytes Reverts Cell Aberrancies and Prevents Paracrine Pathogenicity on Microglia and Motor Neurons

“…VS treatment exceeded the beneficial effects of pre-miR-146a treatment by promoting MN functionality through upregulation of synaptophysin, PSD-95, dynein and kinesin transcripts and by avoiding early cell death by apoptosis. This is in line with a previous study describing vinyl sulfones as neuroprotective agents in the treatment of Parkinson's disease (Woo et al, 2014;Choi et al, 2019). Increased levels of miR-146a in MNs were observed after treatment with the secretome from the pre-miR-146a-treated mSOD1 astrocytes, but not with that from VS treatment.…”

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

“…Activation of Nrf2 may have therapeutic potential for neurodegenerative diseases, such as Parkinson's disease (PD). Based on a previously characterized neuroprotective vinyl sulfone lead structure, Choi et al's optimization efforts included introduction of nitrogen heterocycles to improve activity as well as drug‐like properties . The most promising drug candidate was a morpholine‐containing compound 54 (Figure ), that showed in vitro an EC 50 of 346 nM (1.5‐fold higher activity than the lead compound) with a dose‐dependent induction of expression of Nrf2‐dependent antioxidant enzymes (both at mRNA and protein levels).…”

“…Among other activities, its neuroprotective properties included attenuation of the loss of tyrosine hydroxylase‐immunopositive dopaminergic neurons and the alleviation of Parkinson's disease‐associated motor dysfunction in vivo. Combined with the excellent drug‐like properties, as shown by its ADME/Tox profile, compound 54 may be an agent with therapeutic interest for PD …”

A Novel Synthetic Precursor of Styryl Sulfone Neuroprotective Agents Inhibits Neuroinflammatory Responses and Oxidative Stress Damage through the P38 Signaling Pathway in the Cell and Animal Model of Parkinson’s Disease

“…Recently, the vinyl sulfone group is often also reported in the skeletal structures of many promising neuroprotective agents, including 5-HT6 receptor antagonists [14] and caspase-6 inhibitors [15]. Besides, styryl sulfone small molecules show low toxicity and good blood-brain barrier permeability into the central nervous system (CNS) [16], which will be more efficient in the treatment of neurodegenerative disease. It is believed that oxidative stress and neuroinflammation are major contributors that induce the onset of PD [17].…”