NIBR-0213 / Novartis - LARVOL DELTA

Sphingosine-1-phosphate receptor signaling can regulate synaptic activity of corticotropin-releasing hormone expressing neurons in the central amygdala from chronic pain mice (Neuroscience 2025) - "An S1PR1 antagonist, NIBR-0213, had no effect on sEPSCs recorded from CeACRH+ neurons from either sham or SNI mice, indicating there is possibly a mechanism during SNI which causes internalization of S1PR1 on presynaptic excitatory inputs to CeACRH+ neurons...We propose this differential modulation is due to differential S1PR1 expression. These findings implicate CeACRH+ in the processing of neuropathic pain and identify S1PR1s as a potential target for the development of new analgesic pharmacotherapies."

Preclinical • CNS Disorders • Neuralgia • Pain • S1PR1

The S1P/S1P1 Signaling Axis Plays Regulatory Functions in the Crosstalk Between Brain-Metastasizing Melanoma Cells and Microglia. (PubMed, Cancers (Basel)) - "S1P1 contributes to the immunosuppressive phenotype of microglia. Inhibiting the S1P/S1P1 axis impairs viability and crosstalk between melanoma cells and tumor-activated microglia, offering a potential therapeutic strategy for melanoma brain metastases."

Journal • Melanoma • Oncology • Solid Tumor • CD163 • FCGR2A • FCGR2B • IL6 • JUNB • PD-L1 • S1PR1 • SOCS3 • TGFBR1 • TGFBR2

Dissociation between the anti-allodynic effects of fingolimod (FTY720) and desensitization of S1P1 receptor-mediated G-protein activation in a mouse model of sciatic nerve injury. (PubMed, Neuropharmacology) - "In contrast, the S1PR1-selective antagonist NIBR-0213 prevented the anti-allodynic effect of FTY720, but NIBR-0213 given alone did not affect nociception. These results indicate that FTY720 alleviates CCI-induced allodynia through a mechanism distinct from functional antagonism."

Journal • Preclinical • Metabolic Disorders • Neuralgia • Pain • S1PR1

Endothelial Cell Sphingosine 1-Phophate Receptor 1 Restrains VE-cadherin Cleavage and Attenuates Experimental Inflammatory Arthritis (ACR Convergence 2023) - " VE-cad-a-cat mice were treated with the S1PR1 antagonist NIBR-0213 (30 mg/kg IM) for 3 hours... We present a model in which EC S1PR1 signaling restrains the shedding of VE-cadherin to maintain homeostatic vascular barrier function and curb inflammation in experimental arthritis. Our hypothesis that vascular permeability is a clinical target in RA is supported by evidence that patients have dysregulated S1P/ S1PR1. We identify the microvascular barrier as a potential therapeutic target in inflammatory arthritis."

Immunology • Inflammation • Inflammatory Arthritis • Lupus • Rheumatoid Arthritis • Rheumatology • Systemic Lupus Erythematosus • CDH5 • S1PR1

Quantitative Analysis of S1PR1 Expression in the Postmortem Multiple Sclerosis Central Nervous System. (PubMed, ACS Chem Neurosci) - "Our blocking study using NIBR-0213, a S1PR1 antagonist, indicated [H]CS1P1 is highly specific to S1PR1. Our findings demonstrated the activation of S1PR1 and an increased uptake of [H]CS1P1 in the lesions of MS CNS. In summary, our quantitative autoradiography analysis using [H]CS1P1 on human postmortem tissues shows the feasibility of novel imaging strategies for MS by targeting S1PR1."

Journal • CNS Disorders • Inflammation • Multiple Sclerosis • S1PR1

Spinal S1PR1 Agonism Reduces Neuropathic Pain in Multiple Sclerosis (Neuroscience 2022) - "Preliminary data demonstrates that i.t. injection of fingolimod, the S1PR1 agonist CYM5442, or the S1PR1/R5 agonist BAF-312 each decrease EAE-induced mechanical allodynia...Following the development of allodynia, mice received an intrathecal injection of either fingolimod (1ug/5ul), SEW2871 (1ug/5ul), the S1PR1 antagonist NIBR0213 (1.5ug/5ul), fingolimod+NIBR0213 (5ul), or vehicle (5ul) followed by assessment of mechanical allodynia from 30-120 minutes post injection...We conclude that the spinal cord engages S1PR1 agonism to reduce mechanical allodynia in the EAE model of neuropathic pain. These results point to spinal S1PR1 as a target for future pharmacotherapy of multiple sclerosis associated neuropathic pain."

CNS Disorders • Neuralgia • Pain • S1PR1

Sphk1 and Sphk2 Differentially Regulate Erythropoietin Synthesis in Mouse Renal Interstitial Fibroblast-like Cells. (PubMed, Int J Mol Sci) - "Exogenous sphingosine (Sph) enhanced HIF-2α and Epo, and this was abolished by the combined treatment with the selective S1P and S1P antagonists NIBR-0213 and TY52156, suggesting that Sph was taken up by cells and converted to iS1P and exported to then act in an autocrine manner through S1P and S1P...While accumulation of intracellular Sph reduces Epo synthesis, iS1P will be exported to act through S1P to enhance Epo synthesis. Furthermore, these data suggest that selective inhibition of Sphk2 is an attractive new option to enhance Epo synthesis and thereby to reduce anemia development in chronic kidney disease."

Journal • Preclinical • Chronic Kidney Disease • Gastrointestinal Cancer • Hematological Disorders • Hepatocellular Cancer • Liver Cancer • Nephrology • Renal Disease • Solid Tumor • EPAS1

PET Study of Sphingosine-1-phosphate Receptor 1 Expression in Response to S. aureus Infection. (PubMed, Mol Imaging) - "The specificity of [F]TZ4877 was assessed using S1PR1-specific antagonist, NIBR-0213, and S1PR1-specific DsiRNA pretreated the animals...The uptake of [F]TZ4877 is tightly correlated with the S1R1 expression in response to S. aureus infection. PET with S1PR1-specific radiotracer [F]TZ4877 could provide a noninvasive tool for detecting the early S1PR1 immune response to infectious diseases."

Journal • Infectious Disease • Inflammation • Respiratory Diseases

[VIRTUAL] Enhancing Endothelial Cell Barrier Function via Sphingosine -1 Phosphate Receptor 1 (S1PR1) – a Novel Treatment for Experimental Arthritis (ACR-CONVERGENCE 2021) - "To determine how pharmacologic modulation of S1PR1 signaling affected SIA, WT animals were treated with S1PR1 agonist, CYM-5442 or antagonist NIBR-0213 30 mg/kg or vehicle controls... Our data reveal that S1PR1 signaling restrains VE-cadherin shedding and maintains EC vascular barrier function and thereby attenuates arthritis. Augmenting EC S1PR1 signaling is a potential novel, non-immunosuppressive approach to treat inflammatory arthritis."

Immunology • Inflammatory Arthritis • Rheumatology • CDH5

S1P Stimulates Erythropoietin Production in Mouse Renal Interstitial Fibroblasts by S1P and S1P Receptor Activation and HIF-2α Stabilization. (PubMed, Int J Mol Sci) - "Furthermore, the approved S1P receptor modulator FTY720, and its active form FTY720-phosphate, both exerted a similar effect on Epo expression as S1P. The effect of S1P on Epo was antagonized by the selective S1P and S1P antagonists NIBR-0213 and TY-52156, but not by the S1P antagonist JTE-013...In summary, these data suggest that, in renal interstitial fibroblasts, which are the primary source of plasma Epo, S1P receptor activation upregulates Epo under normoxic conditions. This may have a therapeutic impact on disease situations such as chronic kidney disease, where Epo production is impaired, causing anemia, but it may also have therapeutic value as Epo can mediate additional tissue-protective effects in various organs."

Journal • Preclinical • Chronic Kidney Disease • Hematological Disorders • Nephrology • Neuroblastoma • Oncology • Renal Disease • Solid Tumor • EPAS1 • EPO

Hyperoxia-induced S1P signaling reduced angiogenesis by suppression of TIE-2 leading to experimental bronchopulmonary dysplasia. (PubMed, Cell Biochem Biophys) - "HO induces S1P followed by reduced expression of angiogenic factors. Reduction of S1P signaling restores ANG-1/ TIE-2 signaling leading to improved angiogenesis and alveolarization thus protecting against HO-induced neonatal lung injury."

Journal • Bronchopulmonary Dysplasia • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • ANGPT1

[VIRTUAL] Sphingosine-1-Phosphate-Receptor-1 Modulators’ Effects on Chronic Constrictive Injury (IASP 2021) - "The findings that acute Fingolimod administration reverses mechanical hypersensitivity through an S1P1 receptor-dependent mechanism and does not produce tolerance following repeated administration suggests that this receptor may hold promise as a potential target for the treatment of neuropathic pain, without abuse liability due to tolerance."

CNS Disorders • Immunology • Multiple Sclerosis • Neuralgia • Pain • Peripheral Neuropathic Pain

Siponimod (BAF312) Activates Nrf2 While Hampering NFκB in Human Astrocytes, and Protects From Astrocyte-Induced Neurodegeneration. (PubMed, Front Immunol) - "Interestingly, despite potential glial susceptibility to S1P signaling via S1P3, which is not targeted by BAF312, NFκB translocation and downregulation of glutamate transporters in response to S1P were inhibited at similar levels by BAF312 and FTY720, another S1P signaling modulator targeting also S1P3. Accordingly, specific inhibition of S1P1 via NIBR-0213 blocked S1P-evoked NFκB translocation, demonstrating that modulation of S1P1 is sufficient to dampen signaling via other S1P receptors...Finally, in vitro experiments with spinal neurons exposed to astrocyte-conditioned media showed that modulation of S1P or cytokine signaling in astrocytes via BAF312 prevented neurons from astrocyte-induced degeneration. Overall, these experiments on human astrocytes suggest that during neuroinflammation targeting of S1P1 via BAF312 may modulate key astrocyte functions and thereby attain neuroprotection indirectly."

Journal • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • Solid Tumor • IL17A

Protective effect of the sphingosine-1 phosphate receptor agonist siponimodon disrupted blood brain barrier function. (PubMed, Biochem Pharmacol) - "In contrast, at this time point, activation of S1P5 with the selective agonist UC-42-WP04 (300 nM) or with BAF-312, under blockade of S1P1 with the selective antagonist NIBR-0213 (1 μM), resulted in recovery of expression and localization of claudin-5 and reduction of TNFα/INFγ-induced expression of metalloproteinase 9. The PI3K inhibitor LY294002 (10 µM) prevented in fact the effects of BAF-312 on all the parameters examined. In conclusion, BAF-312, by modulating both S1P1 and S1P5, may strengthen BBB properties, thus providing additional effects in the treatment of MS."

Journal • CNS Disorders • Multiple Sclerosis • IFNG • TNFA