Amiselimod
Amiselimod (MT-1303) is converted to its active metabolite Amiselimod phosphate by sphingosine kinases in vivo. Amiselimod is an orally active and high selectivity sphingosine 1-phosphate receptor-1 (S1P1) agonist, designed to reduce the bradycardia effects associated with fingolimod and other S1P receptor modulators. Amiselimod inhibits chronic colitis via inhibiting infiltration of colitogenic Th1 and Th17 cells into the colon. Amiselimod inhibits lupus nephritis by reducing the infiltration of autoreactive T cells into the kidneys. Amiselimodis promising for research of autoimmune diseases.
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- CAS No.: 942399-20-4
- Formule: C19H30F3NO3
- Masse moléculaire:377.44
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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Chemical Information
- Pureté et documentation
- Références
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Help & FAQs
Activité biologique
Amiselimod (100 nM, 12 h) is converted into Amiselimod-P in HEK293 cells or primary HCMs (human cardiac myocytes) more slowly than Fingolimod (HY-11063) was converted into fingolimod-P[1].
Amiselimod-P (0.001-1000 nM) shows agonist activity at S1P1 receptor with an EC50 of 75 pM, and is more potent than at S1P4 and S1P5 receptors but has no distinct agonist activity at S1P2 or S1P3 receptors in human S1P receptor-expressing cells[1].
Amiselimod-P (0.001-1000 nM) increases G-protein-activated inwardly rectifying potassium (GIRK) current amplitude in a concentration-dependent manner, with an EC50 of 41.6 nM in human atrial myocytes[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Amiselimod (0.3-30 mg/kg, p.o., with a 6 day interval between vehicle and 0.3 mg/kg, 13 or 14 day intervals between dose levels of 0.3, 3 and 30 mg/kg) hydrochloride does not affect heart rate or ECG parameters in monkeys[1].
Amiselimod (0.3 mg/kg, p.o., daily, 3 days) decreases S1P1 expression on CD4+ T cells from mesenteric lymph nodes in C57BL/6 mice[3].
. Amiselimod (0.3 mg/kg, p.o., daily, 28 days) inhibits the development of colitis induced by adoptive transfer of CD4+CD45RBhigh T cells in SCID mice[3].
Amiselimod (0.3 mg/kg, p.o., daily, 3-4 weeks) reduces infiltration of Th1 and Th17 cells into the colon of colitis mic e induced by adoptive transfer of CD4+CD45RBhigh T cells [3].
Amiselimod (0.1-0.3 mg/kg, p.o., daily, 21 days) inhibits the development of chronic colitis with an efficacy comparable to that of an anti-mTNF-α mAb (250 μg/mouse) in adoptive transfer of CD4+CD45RBhigh T cells induced colitis mice[3].
Amiselimod (0.1-1 mg/kg, p.o., daily, 18 weeks) strongly inhibits the development of lupus nephritis in MRL/lpr mice[4].
Amiselimod (0.1-0.3 mg/kg, p.o., daily, 10 weeks) prevents progression of lupus nephritis in NZBWF1 Mice[4].
Amiselimod (0.3 mg/kg, p.o., daily, 13 weeks) reduces infiltration of T Cells into the kidneys of NZBWF1 mice[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Four male cynomolgus monkeys, Macaca fascicularis, 3-4 years old [1].
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Dosage:0.3, 3, 30 mg/kg
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Administration:p.o., with a 6 day interval between vehicle and 0.3 mg/kg, 13 or 14 day intervals between dose levels of 0.3, 3 and 30 mg/kg.
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Result:Had no effects on heart rate or ECG parameters, including PR interval, QRS duration, QT interval and QTc at doses up to 30 mg/kg
Did not affect blood pressure at doses up to 30 mg/kg.
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Animal Model:Male C57BL/6 mice, aged 5 weeks[3].
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Dosage:0.3 mg/kg
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Administration:p.o., daily, 3 days
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Result:Decreased S1P1 expression on CD4+ T cells from mesenteric lymph nodes.
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Animal Model:Immunodeficient SCID mice with chronic colitis induced by adoptive transfer of CD4+CD45RBhigh T cells from BALB/c mice[3].
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Dosage:0.1, 0.3 mg/kg
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Administration:p.o., daily, 28 days
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Result:Body weight remained higher than that in the control group from 4 days after cell transfer.
Body weight in the 0.3 mg/kg treated group was significantly higher than that in the control group from 17 days.
Clinical scores (sum of scores for hunching, wasting, colon thickening, and stool consistency) in the 0.1 and 0.3 mg/kg treated groups were 1.5 and 1.1.
Reduced inflammatory cell infiltrates, epithelial hyperplasia and mucin depletion from goblet cells in the colon at 0.3 mg/kg.
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Animal Model:Immunodeficient SCID mice with chronic colitis induced by adoptive transfer of CD4+CD45RBhigh T cells from BALB/c mice[3].
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Dosage:0.1, 0.3 mg/kg
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Administration:p.o., daily, 21 days, the anti-mTNF-α mAb (250 μg/mouse) was intraperitoneally injected on days 7 and 21.
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Result:Increased body weight from day 15 comparable to anti-mTNF-α mAb-treated groups.
Clinical scores in the 0.1 and 0.3 mg/kg treated groups were 1.1 and 0.6 and anti-mTNF-α mAb-treated group was 1.2.
Inhibited the development of chronic colitis with an efficacy comparable to that of an anti-mTNF-α mAb (250 μg/mouse).
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Animal Model:Immunodeficient SCID mice with chronic colitis induced by adoptive transfer of CD4+CD45RBhigh T cells from BALB/c mice[3].
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Dosage:0.3 mg/kg
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Administration:p.o., daily, 3-4 weeks
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Result:Significantly reduced the number of infiltrating lymphocytes and CD4+ T cells.
Decreased the number of IFN-γ- and IL-17-producing CD4+ T cells in the lamina propria.
Produced significantly less IFN-γ and IL-17 than those from vehicle-treated mice.
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Animal Model:MRL/lpr mice at 8 weeks of age without proteinuria[4].
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Dosage:0.1, 0.3, 1 mg/kg
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Administration:p.o., daily, 18 weeks
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Result:No mice treated at doses greater than 0.3 mg/kg developed lupus nephritis during the study period.
Reduced this infiltration of T cells into the kidneys.
Inhibited the development of lymphadenopathy and splenomegaly.
Decreased the number of T cells,CD4 T cells, B cells, and MRL/lpr-mouse-specific abnormal T cells.
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Animal Model:NZBWF1 mice at 30 weeks of age without proteinuria[4].
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Dosage:0.1, 0.3 mg/kg
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Administration:p.o., daily, 10 weeks
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Result:Mean proteinuria scores remained lower than those in the control group.
Attenuated the severity of several histological changes including mesangial expansion, glomerular sclerosis, and interstitial infiltrates.
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Animal Model:NZBWF1 mice at 41 weeks of age without proteinuria[4].
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Dosage:0.3 mg/kg
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Administration:p.o., daily, 13 weeks
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Result:Reduced the number of infiltrating T cells, CD4 T cells, CD8 T cells, and CD4-CD8- double-negative (DN) T cells.
Decreased B cell counts.
| NCT Number | Sponsor | Condition | Start Date |
Phase
|
|---|---|---|---|---|
| NCT01329991 | Plexxikon| | 2011-05 | PHASE1 |
Chemical Information
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CAS No. 942399-20-4
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Masse moléculaire 377.44
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Formule C19H30F3NO3
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SMILES
FC(F)(C1=CC(CCC(CO)(CO)N)=CC=C1OCCCCCCC)F
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Synonyms
MT-1303
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
[1]. Sugahara K, et al., Amiselimod, a novel sphingosine 1-phosphate receptor-1 modulator, has potent therapeutic efficacy for autoimmune diseases, with low bradycardia risk. Br J Pharmacol. 2017 Jan;174(1):15-27. [Content Brief]
[2]. Kappos L, et al. Safety and efficacy of amiselimod in relapsing multiple sclerosis (MOMENTUM): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2016 Oct;15(11):1148-59. [Content Brief]
[3]. Shimano K, et al. Amiselimod (MT-1303), a novel sphingosine 1-phosphate receptor-1 functional antagonist, inhibits progress of chronic colitis induced by transfer of CD4+CD45RBhigh T cells. PLoS One. 2019 Dec 5;14(12):e0226154. [Content Brief]
[4]. Sugahara K, et al. Amiselimod (MT-1303), a Novel Sphingosine 1-Phosphate Receptor-1 Modulator, Potently Inhibits the Progression of Lupus Nephritis in Two Murine SLE Models. J Immunol Res. 2019 Dec 23;2019:5821589. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Amiselimod Related Classifications
HY-16734 Related Classifications
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