Ceralifimod
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MedKoo CAT#: 206453

CAS#: 891859-12-4

Description: Ceralifimod, also known as ONO-4641, is a next-generation sphingosine 1-phosphate (S1P) receptor agonist selective for S1P receptors 1 and 5. In vitro, ONO-4641 showed highly potent agonistic activities versus S1P receptors 1 and 5 [half maximal effective concentration (EC(50) ) values of 0·0273 and 0·334 nM, respectively]. ONO-4641 decreased peripheral blood lymphocyte counts in rats by inhibiting lymphocyte egress from secondary lymphoid tissues. ONO-4641 prevented relapse of disease in a non-obese diabetic mouse model of relapsing-remitting EAE. ONO-4641 may provide therapeutic benefits in the treatment of multiple sclerosis.

Chemical Structure

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Ceralifimod
CAS# 891859-12-4
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 206453
Name: Ceralifimod
CAS#: 891859-12-4
Chemical Formula: C27H33NO4
Exact Mass: 435.24
Molecular Weight: 435.560
Elemental Analysis: C, 74.45; H, 7.64; N, 3.22; O, 14.69

Price and Availability

Size Price Availability Quantity
10mg USD 110 Ready to ship
25mg USD 245 Ready to ship
50mg USD 440 Ready to ship
100mg USD 750 Ready to ship
200mg USD 1250 Ready to ship
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Synonym: ONO-4641; ONO 4641; ONO4641; Ceralifimod

IUPAC/Chemical Name: 1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxylic acid

InChi Key: QDDQIPUKAXBMBX-UHFFFAOYSA-N

InChi Code: InChI=1S/C27H33NO4/c1-4-5-19-6-7-22(26(12-19)31-3)17-32-24-10-11-25-18(2)21(9-8-20(25)13-24)14-28-15-23(16-28)27(29)30/h6-7,10-13,23H,4-5,8-9,14-17H2,1-3H3,(H,29,30)

SMILES Code: CCCC1=CC=C(COC2=CC(CCC(CN3CC(C(O)=O)C3)=C4C)=C4C=C2)C(OC)=C1

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:

Biological target: Ceralifimod (ONO-4641) is selective, high potent agonist for sphingosine 1-phosphate receptors 1 and 5, with EC50s of 27.3, 334 pM for human S1P receptor 1 and 5, respectively.
In vitro activity: The objective of the study was to characterize the immunomodulatory effects of ONO-4641 using preclinical data. ONO-4641 was tested in-vitro pharmacological studies. In order to investigate the binding affinity of ONO-4641 for S1P receptors, competitive binding experiments of this substance were performed for the specific binding of [33P]-S1P to S1P receptors (Table 1). ONO-4641 inhibited the specific binding of [33P]-S1P to hS1P1 and hS1P5 in a concentration-dependent manner, with Ki values of 0·626 and 0·574 nM, respectively. ONO-4641 also inhibited the specific binding to hS1P4, but the Ki value of ONO-4641 was 28·8 nM, approximately 50 times higher than those for hS1P1 and hS1P5. Conversely, the inhibitory rate of ONO-4641 on the specific binding of [33P]-S1P to hS1P2 and hS1P3 was less than 50% even at a concentration of 10 μM. To investigate the species difference between human and rat, the binding affinity of ONO-4641 for rS1P1 was examined. The Ki value of ONO-4641 for rS1P1 was 0·772 nM, indicating that ONO-4641 has a high binding affinity for rS1P1 comparable to that for hS1P1 (Table 1). We examined whether ONO4641 also induces S1P1 down-regulation on the cell membrane. Both the natural ligand S1P and S1P1-selective agonist SEW2871 were used as control. In cells expressing S1P1, ONO-4641 induced S1P1 down-regulation in a concentration-dependent manner and by approximately 90% at concentration of 25 nM (Fig. 1a). S1P and SEW2871 also decreased the expression of S1P1 receptors on the cell membrane. The EC50 values of ONO-4641, S1P, and SEW2871 were 0·778, 132 and 118 nM, respectively (Fig. 1b). Clin Exp Immunol. 2013 Jan; 171(1): 54–62. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530095/
In vivo activity: In this study, the S1P receptor modulator ONO-4641 induced the expansion of lung CD11b+Gr-1+ cells and lymphocytopenia was demonstrated in naive mice. ONO-4641-expanded CD11b+Gr-1+ cells showed higher arginase-1 activity, decreased T cell proliferation, and lower IFN-γ production in CD3+ T cells, similar to the features of myeloid-derived suppressor cells. ONO-4641 treatment decreased airspace enlargement in elastase-induced and cigarette smoke-induced emphysema models and attenuated emphysema exacerbation induced by post-elastase pneumococcal infection, which was also associated with an increased number of lung CD11b+Gr-1+ cells. Adoptive transfer of ONO-4641-expanded CD11b+Gr-1+ cells protected against elastase-induced emphysema. Lymphocytopenia observed in these models likely contributed to beneficial ONO-4641 effects. Thus, ONO-4641 attenuated murine pulmonary emphysema by expanding lung CD11b+Gr-1+ cell populations and inducing lymphocytopenia. The S1P receptor might be a promising target for strategies aimed at ameliorating pulmonary emphysema progression. Mucosal Immunol. 2018 Nov;11(6):1606-1620. https://pubmed.ncbi.nlm.nih.gov/30116000/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 5.0 11.48

Preparing Stock Solutions

The following data is based on the product molecular weight 435.56 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Komiya T, Sato K, Shioya H, Inagaki Y, Hagiya H, Kozaki R, Imai M, Takada Y, Maeda T, Kurata H, Kurono M, Suzuki R, Otsuki K, Habashita H, Nakade S. Efficacy and immunomodulatory actions of ONO-4641, a novel selective agonist for sphingosine 1phosphate receptors 1 and 5, in preclinical models of multiple sclerosis. Clin Exp Immunol. 2013 Jan;171(1):54-62. doi: 10.1111/j.1365-2249.2012.04669.x. PMID: 23199323; PMCID: PMC3530095. 2. Ohno T, Hasegawa C, Nakade S, Kitagawa J, Honda N, Ogawa M. The prediction of human response to ONO-4641, a sphingosine 1-phosphate receptor modulator, from preclinical data based on pharmacokinetic-pharmacodynamic modeling. Biopharm Drug Dispos. 2010 Oct;31(7):396-406. doi: 10.1002/bdd.719. PMID: 20623701. 3. Komiya T, Gohda M, Shioya H, Katsumata S. Sphingosine 1-Phosphate Receptor Modulator ONO-4641 Regulates Trafficking of T Lymphocytes and Hematopoietic Stem Cells and Alleviates Immune-Mediated Aplastic Anemia in a Mouse Model. J Pharmacol Exp Ther. 2021 Feb;376(2):250-260. doi: 10.1124/jpet.120.000277. Epub 2020 Nov 30. PMID: 33257316. 4.Asakura T, Ishii M, Namkoong H, Suzuki S, Kagawa S, Yagi K, Komiya T, Hashimoto T, Okamori S, Kamata H, Tasaka S, Kihara A, Hegab AE, Hasegawa N, Betsuyaku T. Sphingosine 1-phosphate receptor modulator ONO-4641 stimulates CD11b+Gr-1+ cell expansion and inhibits lymphocyte infiltration in the lungs to ameliorate murine pulmonary emphysema. Mucosal Immunol. 2018 Nov;11(6):1606-1620. doi: 10.1038/s41385-018-0077-5. Epub 2018 Aug 16. PMID: 30116000.
In vitro protocol: 1. Komiya T, Sato K, Shioya H, Inagaki Y, Hagiya H, Kozaki R, Imai M, Takada Y, Maeda T, Kurata H, Kurono M, Suzuki R, Otsuki K, Habashita H, Nakade S. Efficacy and immunomodulatory actions of ONO-4641, a novel selective agonist for sphingosine 1phosphate receptors 1 and 5, in preclinical models of multiple sclerosis. Clin Exp Immunol. 2013 Jan;171(1):54-62. doi: 10.1111/j.1365-2249.2012.04669.x. PMID: 23199323; PMCID: PMC3530095. 2. Ohno T, Hasegawa C, Nakade S, Kitagawa J, Honda N, Ogawa M. The prediction of human response to ONO-4641, a sphingosine 1-phosphate receptor modulator, from preclinical data based on pharmacokinetic-pharmacodynamic modeling. Biopharm Drug Dispos. 2010 Oct;31(7):396-406. doi: 10.1002/bdd.719. PMID: 20623701.
In vivo protocol: 1. Komiya T, Gohda M, Shioya H, Katsumata S. Sphingosine 1-Phosphate Receptor Modulator ONO-4641 Regulates Trafficking of T Lymphocytes and Hematopoietic Stem Cells and Alleviates Immune-Mediated Aplastic Anemia in a Mouse Model. J Pharmacol Exp Ther. 2021 Feb;376(2):250-260. doi: 10.1124/jpet.120.000277. Epub 2020 Nov 30. PMID: 33257316. 2. Asakura T, Ishii M, Namkoong H, Suzuki S, Kagawa S, Yagi K, Komiya T, Hashimoto T, Okamori S, Kamata H, Tasaka S, Kihara A, Hegab AE, Hasegawa N, Betsuyaku T. Sphingosine 1-phosphate receptor modulator ONO-4641 stimulates CD11b+Gr-1+ cell expansion and inhibits lymphocyte infiltration in the lungs to ameliorate murine pulmonary emphysema. Mucosal Immunol. 2018 Nov;11(6):1606-1620. doi: 10.1038/s41385-018-0077-5. Epub 2018 Aug 16. PMID: 30116000.

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1: Roy R, Alotaibi AA, Freedman MS. Sphingosine 1-Phosphate Receptor Modulators for Multiple Sclerosis. CNS Drugs. 2021 Apr;35(4):385-402. doi: 10.1007/s40263-021-00798-w. Epub 2021 Apr 2. PMID: 33797705.


2: Krösser S, Wolna P, Fischer TZ, Boschert U, Stoltz R, Zhou M, Darpo B. Effect of ceralifimod (ONO-4641) on lymphocytes and cardiac function: Randomized, double-blind, placebo-controlled trial with an open-label fingolimod arm. J Clin Pharmacol. 2015 Sep;55(9):1051-60. doi: 10.1002/jcph.513. Epub 2015 May 25. PMID: 25855155.


3: Gonzalez-Cabrera PJ, Brown S, Studer SM, Rosen H. S1P signaling: new therapies and opportunities. F1000Prime Rep. 2014 Dec 1;6:109. doi: 10.12703/P6-109. PMID: 25580263; PMCID: PMC4251414.


4: Kurata H, Kusumi K, Otsuki K, Suzuki R, Kurono M, Komiya T, Hagiya H, Mizuno H, Shioya H, Ono T, Takada Y, Maeda T, Matsunaga N, Kondo T, Tominaga S, Nunoya KI, Kiyoshi H, Komeno M, Nakade S, Habashita H. Discovery of a 1-Methyl-3,4-dihydronaphthalene-Based Sphingosine-1-Phosphate (S1P) Receptor Agonist Ceralifimod (ONO-4641). A S1P1 and S1P5 Selective Agonist for the Treatment of Autoimmune Diseases. J Med Chem. 2017 Dec 14;60(23):9508-9530. doi: 10.1021/acs.jmedchem.7b00785. Epub 2017 Nov 21. PMID: 29120624.


5: Subei AM, Cohen JA. Sphingosine 1-phosphate receptor modulators in multiple sclerosis. CNS Drugs. 2015 Jul;29(7):565-75. doi: 10.1007/s40263-015-0261-z. PMID: 26239599; PMCID: PMC4554772.


6: Dash RP, Srinivas NR, Rais R. A review of bioanalytical quantitative methods for selected sphingosine 1-phosphate receptor modulators. Biomed Chromatogr. 2018 Jan;32(1). doi: 10.1002/bmc.4109. Epub 2017 Nov 6. PMID: 28990207.


7: Chaudhry BZ, Cohen JA, Conway DS. Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis. Neurotherapeutics. 2017 Oct;14(4):859-873. doi: 10.1007/s13311-017-0565-4. PMID: 28812220; PMCID: PMC5722770.


8: O'Sullivan S, Dev KK. Sphingosine-1-phosphate receptor therapies: Advances in clinical trials for CNS-related diseases. Neuropharmacology. 2017 Feb;113(Pt B):597-607. doi: 10.1016/j.neuropharm.2016.11.006. Epub 2016 Nov 4. PMID: 27825807.


9: Shioya H, Inagaki Y, Hiraizumi K, Hoshino T, Kurata H, Habashita H, Sato K, Nakade S. Preventive and Therapeutic Efficacy of ONO-4641, a Selective Agonist for Sphingosine 1-Phosphate Receptor 1 and 5, in Preclinical Models of Type 1 Diabetes Mellitus. Biol Pharm Bull. 2021;44(2):188-196. doi: 10.1248/bpb.b20-00580. PMID: 33518672.


10: Dannhorn A, Ling S, Powell S, McCall E, Maglennon G, Jones GN, Pierce AJ, Strittmatter N, Hamm G, Barry ST, Bunch J, Goodwin RJA, Takats Z. Evaluation of UV-C Decontamination of Clinical Tissue Sections for Spatially Resolved Analysis by Mass Spectrometry Imaging (MSI). Anal Chem. 2021 Feb 9;93(5):2767-2775. doi: 10.1021/acs.analchem.0c03430. Epub 2021 Jan 21. PMID: 33474935.


11: Komiya T, Gohda M, Shioya H, Katsumata S. Sphingosine 1-Phosphate Receptor Modulator ONO-4641 Regulates Trafficking of T Lymphocytes and Hematopoietic Stem Cells and Alleviates Immune-Mediated Aplastic Anemia in a Mouse Model. J Pharmacol Exp Ther. 2021 Feb;376(2):250-260. doi: 10.1124/jpet.120.000277. Epub 2020 Nov 30. PMID: 33257316.


12: Asakura T, Ishii M, Namkoong H, Suzuki S, Kagawa S, Yagi K, Komiya T, Hashimoto T, Okamori S, Kamata H, Tasaka S, Kihara A, Hegab AE, Hasegawa N, Betsuyaku T. Sphingosine 1-phosphate receptor modulator ONO-4641 stimulates CD11b+Gr-1+ cell expansion and inhibits lymphocyte infiltration in the lungs to ameliorate murine pulmonary emphysema. Mucosal Immunol. 2018 Nov;11(6):1606-1620. doi: 10.1038/s41385-018-0077-5. Epub 2018 Aug 16. PMID: 30116000.


13: Ohno T, Hasegawa C, Nakade S, Kitagawa J, Honda N, Ogawa M. The prediction of human response to ONO-4641, a sphingosine 1-phosphate receptor modulator, from preclinical data based on pharmacokinetic-pharmacodynamic modeling. Biopharm Drug Dispos. 2010 Oct;31(7):396-406. doi: 10.1002/bdd.719. PMID: 20623701.