Researchers developed new sphingosine-1-phosphate-1 (S1P1) receptor agonists called 21l and 21m as potential treatments for multiple sclerosis (MS), as published in the Journal of Medicinal Chemistry. They showed significantly reduced lymphocyte counts in rats.
The molecules were also able to delay disease onset and reduce disease incidence in a myelin oligodendrocyte glycoprotein35−55-induced experimental autoimmune encephalitis (EAE) mouse model. Both treatments showed significantly lower daily mean clinical scores compared to mice given only the treatment vehicle.
The treated mice also had a significant reduction in attenuated cumulative scores and mean maximum scores, which indicated a reduction in disease severity.
The mice receiving treatment had a reduction in weight loss compared to the vehicle mice. Mice in an EAE model typically lose weight due to increased inflammatory reactions and a reduction in food intake due to paralysis. The treatments also appeared to work in a dose-dependent manner with 21l being slightly superior to 21m.
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“Treatment of EAE mice with 21l effectively ameliorated the disease progression and MS’s severity, suggesting that 21l is a novel S1P1 receptor agonist for MS treatment,” the authors said.
In the article, a series of S1P1 receptor agonists were synthesized following the creation of a leading compound called 7k which utilized a novel triazole core scaffold. Optimization of 7k with an isoxazoline ring as a heterocycle core yielded improved 21l and 21m that showed improved S1P1 receptor internalization.
The optimized molecules also showed better recruitment of β-arrestin as well as favorable CYP inhibition and microsomal stability assays. The 2 molecules also had superior pharmacokinetic profiles.
Both 21l and 21m demonstrated in vitro selectivities against the S1P3 receptor which are believed to cause the undesired side effects such as bradycardia and declining pulmonary function seen in the nonselective S1P receptor agonist fingolimod.
Park SJ, Yeon SK, Kim Y, et al. Discovery of novel sphingosine-1-phosphate-1 receptor agonists for the treatment of multiple sclerosis. J Med Chem. Published online January 25, 2022. doi:10.1021/acs.jmedchem.1c01979