Synthesis and Evaluation of Serinolamide Derivatives as Sphingosine-1-Phosphate-1 (S1P1) Receptor Agonists.

Sphingosine-1-phosphate-1 (S1P1) receptor agonists are well-known drugs for treating multiple sclerosis (MS) caused by autoreactive lymphocytes that attack the myelin sheath. Therefore, an effective therapeutic strategy is to reduce the lymphocytes in the blood by inducing S1P1 receptor internalization. We synthesized serinolamide A, a natural product of the sea, and performed S1P1 receptor internalization assay to evaluate functionally antagonistic S1P1 receptor agonist activity. In order to synthesize derivatives with better efficacy than serinolamide A and B, new derivatives were synthesized by introducing the phenyl ring moiety of fingolimod. Among them, compounds 19 and 21 had superior S1P1 agonistic effects to serinolamide. We also confirmed that compound 19 effectively inhibited lymphocyte outflow in peripheral lymphocyte count (PLC) assay.

Optimization and evaluation of pyridinyl vinyl sulfones as Nrf2 activator for the antioxidant and anti-inflammatory effects.

Many studies have reported that chalcone-based compounds exhibit biological activities such as anticancer, antioxidant, anti-inflammatory and neuroprotective effects. Among the published chalcone derivatives, (E)-1-(3-methoxypyridin-2-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (VEDA-1209), which is currently undergoing preclinical study, was selected as a starting compound for the development of new nuclear factor erythroid 2-related factor 2 (Nrf2) activators. Based on our previous knowledge, we attempted to redesign and synthesize VEDA-1209 derivatives by introducing the pyridine ring and sulfone moiety to ameliorate its Nrf2 efficacy and drug-like properties. Among the synthesized compounds, (E)-3-chloro-2-(2-((3-methoxypyridin-2-yl)sulfonyl)vinyl) pyridine (10e) was found to have approximately 16-folds higher Nrf2 activating effects than VEDA-1209 (10e: EC50 = 37.9 nM vs VEDA-1209: EC50 = 625 nM) in functional cell-based assay. In addition, 10e effectively improved drug-like properties such as CYP inhibition probability and metabolic stability. Finally, 10e demonstrated excellent antioxidant and anti-inflammatory effects in BV-2 microglial cells and significantly restored spatial memory deficits in lipopolysaccharide (LPS)-induced neuroinflammatory mouse models.

Discovery of Novel Sphingosine-1-Phosphate-1 Receptor Agonists for the Treatment of Multiple Sclerosis.

The sphingosine-1-phosphate-1 (S1P1) receptor agonists have great potential for the treatment of multiple sclerosis (MS) because they can inhibit lymphocyte egress through receptor internalization. We designed and synthesized triazole and isoxazoline derivatives to discover a novel S1P1 agonist for MS treatment. Of the two scaffolds, the isoxazoline derivative was determined to have excellent in vitro efficacy and drug-like properties. Among them, compound 21l was found to have superior drug-like properties as well as excellent in vitro efficacies (EC50 = 7.03 nM in ß-arrestin recruitment and EC50 = 11.8 nM in internalization). We also confirmed that 21l effectively inhibited lymphocyte egress in the peripheral lymphocyte count test and significantly improved the clinical score in the experimental autoimmune encephalitis MS mouse model.

Development and optimization of halogenated vinyl sulfones as Nrf2 activators for the treatment of Parkinson's disease.

The Kelch-like ECH-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway plays a pivotal role in the cellular defense system against oxidative stress by inducing antioxidant and anti-inflammatory effects. We previously developed Nrf2 activators that potentially protect the death of dopaminergic (DAergic) neuronal cells against oxidative stress in Parkinson's disease (PD). In this study, we designed and synthesized a class of halogenated vinyl sulfones by inserting halogens and pyridine to maximize Nrf2 activation efficacy. Among the synthesized compounds, (E)-3-chloro-2-(2-((2-chlorophenyl)sulfonyl)vinyl)pyridine (9d) significantly exhibited potent Nrf2 activating efficacy (9d: EC50 = 26 nM) at least 10-fold compared with the previous developed compounds (1 and 2). Furthermore, treating with 9d remarkably increased Nrf2 nuclear translocation and Nrf2 protein levels in microglial BV-2 cells. 9d was shown to induce the expression of antioxidant response genes HO-1, GCLC, GCLM, and SOD-1 at both the mRNA and protein levels and suppress proinflammatory cytokines and enzymes. Also, 9d remarkably protected DAergic neurons and restored the PD-associated motor dysfunction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model.

Antioxidant, Anti-inflammatory, and Neuroprotective Effects of Novel Vinyl Sulfonate Compounds as Nrf2 Activator.

The main pathway responsible for cellular regulation against oxidative stress is nuclear factor E2-related factor-2 (Nrf2) signaling. We previously synthesized and reported a novel vinyl sulfone (1) as an Nrf2 activator with therapeutic potential for Parkinson's disease (PD). In this study, we changed the vinyl sulfone to vinyl sulfonamide or vinyl sulfonate to improve Nrf2 activating efficacy. We observed that the introduction of vinyl sulfonamide led to a reduction of the effects on Nrf2 activation, whereas vinyl sulfonate compounds exhibited superior activity compared to the vinyl sulfone compounds. Among the vinyl sulfonates, 3c exhibited 6.9- and 83.5-fold higher effects on Nrf2 activation than the corresponding vinyl sulfone (1) and vinyl sulfonamide (2c), respectively. Compound 3c was confirmed to induce expression of the Nrf2-dependent antioxidant enzymes at the protein level in cells. In addition, 3c mitigated PD-associated behavioral deficits by protecting DAergic neurons in the MPTP-induced mouse model of PD.