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Purity: ≥98%
Amiselimod HCl (formerly also known as MT-1303) is a novel, potent and selective immunosuppressant and sphingosine 1 phosphate receptor (S1P1) modulator. Amiselimod may be helpful in the treatment of psoriasis, inflammatory bowel disorders, autoimmune diseases, inflammatory diseases, and multiple sclerosis. Mitsubishi Tanabe Pharma Corporation is now working on amiselimod to lessen the bradycardia effects of fingolimod and other S1P receptor modulators.
| Targets |
Sphingosine 1-phosphate receptor 1 (S1P₁) functional antagonist/agonist (EC₅₀ = 0.075 nM).
Sphingosine 1-phosphate receptor 5 (S1P₅) agonist (EC₅₀ = 0.47 nM). Sphingosine 1-phosphate receptor 4 (S1P₄) weak agonist (EC₅₀ = 122.3 nM). Sphingosine 1-phosphate receptor 2 (S1P₂) and S1P₃: No distinct agonist activity (EC₅₀ > 10,000 nM). [1] G-protein-activated inwardly rectifying potassium (GIRK) channel activator (EC₅₀ = 41.6 nM for its active metabolite, amiselimod-P). [1] |
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| ln Vitro |
The active metabolite of amiselimod, amiselimod-P, showed potent and selective agonist activity for human S1P₁ (EC₅₀ 0.075 nM) and S1P₅ (EC₅₀ 0.47 nM) receptors, with minimal activity at S1P₄ (EC₅₀ 122.3 nM) and no distinct agonist activity at S1P₂ or S1P₃ receptors (EC₅₀ > 10,000 nM) in a calcium mobilization assay. [1]
Amiselimod-P activated GIRK currents in acutely isolated human atrial myocytes in a concentration-dependent manner with an EC₅₀ of 41.6 nM, which was approximately 5-fold weaker than fingolimod-P (EC₅₀ 8.5 nM) and 20-fold weaker than S1P (EC₅₀ 1.9 nM). [1] In vitro phosphorylation in human embryonic kidney 293 (HEK293) cells and primary human cardiac myocytes (HCMs) showed that the conversion of amiselimod to its active phosphate metabolite (amiselimod-P) was slower than the conversion of fingolimod to fingolimod-P. Amiselimod-P was first detected after 6 hours of incubation, and its concentration after 12 hours was about half that of fingolimod-P generated under the same conditions. [1] |
| ln Vivo |
Amiselimod-P showed potent selectivity for S1P1 and high selectivity for S1P5 receptors, with minimal agonist activity for S1P4 and no distinct agonist activity for S1P2 or S1P3 receptors and approximately five-fold weaker GIRK activation than fingolimod-P. After oral administration of amiselimod or fingolimod at 1 mg·kg-1 , the concentration of amiselimod-P in rat heart tissue was lower than that of fingolimod-P, potentially contributing to the minimal cardiac effects of amiselimod. A telemetry study in monkeys confirmed that amiselimod did not affect heart rate or ECG parameters.
After a single oral administration of amiselimod (1 mg/kg) to rats, the concentration of the active metabolite amiselimod-P in heart tissue was significantly lower compared to fingolimod-P after an equivalent dose of fingolimod. The heart AUC₀–last for amiselimod-P was approximately 1/20th, and the Cmax was about 1/10th of that for fingolimod-P. [1] In a cardiovascular telemetry study in conscious cynomolgus monkeys, oral administration of amiselimod at doses up to 30 mg/kg had no effects on heart rate, ECG parameters (PR, QRS, QT, QTc intervals), or blood pressure. [1] In a phase I clinical trial in healthy human subjects, daily oral administration of amiselimod (0.125–0.75 mg) for 21 days caused a dose-dependent reduction in peripheral blood lymphocyte counts, with a maximum reduction of approximately 60-66% at the 0.5 and 0.75 mg doses by day 21. No clinically significant bradycardia was observed on day 1 or during the study at these doses. [1] |
| Cell Assay |
Calcium Mobilization Assay for S1P Receptor Activity: Cells expressing human S1P receptors (S1P₁₋₅) were loaded with Fura 2-AM in a buffer. After washing, cells were seeded in plates. Test compounds were added, and changes in fluorescence intensity (ratio of 340 nm/380 nm excitation at 540 nm emission) due to intracellular Ca²⁺ mobilization were measured for 210 seconds. Agonist activity was expressed as a percentage of the maximum response induced by S1P. [1]
In Vitro Phosphorylation Assay: HEK293 cells or primary human cardiac myocytes were plated and cultured overnight. Amiselimod or fingolimod was added to the culture at a final concentration of 100 nM. Supernatants were collected at 3, 6, and 12 hours after addition. The concentrations of the phosphorylated active metabolites (amiselimod-P or fingolimod-P) in the supernatants were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) following solid-phase extraction. [1] |
| Animal Protocol |
Tissue Distribution in Rats: Seven-week-old male Sprague-Dawley rats were fasted for 15 hours and then given a single oral dose of amiselimod or fingolimod at 1 mg/kg. At 2, 4, 8, 24, or 48 hours post-dose, rats were anesthetized and killed. Blood was collected for plasma, and hearts were removed and homogenized. Concentrations of the parent drug and its phosphate metabolite in plasma and heart homogenates were measured by LC-MS/MS. [1]
Cardiovascular Telemetry in Monkeys: Male cynomolgus monkeys were surgically implanted with telemetry transmitters to monitor ECG and blood pressure. After recovery, amiselimod was administered orally in a dose-ascending manner (vehicle, 0.3, 3, and 30 mg/kg), with washout intervals between doses. Heart rate and ECG parameters were automatically recorded and analyzed before and at multiple time points up to 72 hours after each dose. [1] Phase I Clinical Trial (Human): This was a randomized, double-blind, placebo-controlled, multiple ascending dose study in healthy male volunteers. Subjects received oral amiselimod (0.125, 0.25, 0.5, or 0.75 mg) or placebo once daily for 21 days in the fed state. Safety assessments, pharmacokinetic blood sampling, lymphocyte counts, and 24-hour Holter ECG monitoring (especially on day 1) were conducted extensively throughout the study and follow-up period. [1] |
| ADME/Pharmacokinetics |
In healthy subjects, the exposures (Cmax and AUC) of amicelilimod and its active metabolite amicelilimod-P increased approximately dose-proportionally across the dose range of 0.125 to 0.75 mg. [1]
Amcelilimod reached its median tmax within 12–16 hours of day 1 and within 6–10 hours of day 21. Amcelilimod-P reached its median tmax within 12 hours of day 1 and within 8–12 hours of day 21. [1] The elimination half-lives (t₁/₂) of both amicelilimod and amicelilimod-P were very long. The mean half-life of amicelilimod was 386 to 423 hours (approximately 16–18 days), and the mean half-life of amicelilimod-P was 376 to 404 hours (approximately 15–17 days). [1] After 21 days of administration, the cumulative ratio of amiselimod was approximately 16–29, and the cumulative ratio of amiselimod-P was approximately 7–9. [1] Renal excretion was minimal. The urinary excretion of amiselimod and amiselimod-P was less than 0.2% and 0.05% of the administered dose, respectively, indicating that non-renal (likely hepatic) clearance was the primary elimination route. [1] In rats, after oral administration of a 1 mg/kg dose, the plasma exposure (AUC) of amiselimod-P was comparable to that of fingolimod-P, but its cardiac tissue exposure (AUC and Cmax) was significantly reduced (1/20 and 1/10, respectively). [1] |
| Toxicity/Toxicokinetics |
Amiselimod was well tolerated in the Phase I clinical trial. Most adverse events were mild (e.g., headache), and no serious or life-threatening adverse events were reported, nor were there any withdrawals from the study due to adverse events. No adverse events were dose-related. [1] Apart from the expected drug-induced decrease in lymphocyte count, no clinically significant abnormalities were reported in laboratory tests, vital signs, pulmonary function tests, or echocardiography. [1] A few subjects treated with amiselimod and in the placebo group experienced transient, asymptomatic atrioventricular conduction abnormalities (Moll's type I/Wenck block, first-degree atrioventricular block). These abnormalities were considered clinically insignificant by the investigators, and no dose-dependent trend was observed. The QTc interval did not exceed 500 ms in any subject, and the increase from baseline did not exceed 60 ms. [1]
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| References |
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| Additional Infomation |
Amiselimod (MT-1303) is a second-generation oral prodrug, a sphingosine-1-phosphate (S1P) receptor modulator. It is converted in vivo by sphingosine kinase to its active phosphate metabolite (S)-amiselimod phosphate (amiselimod-P). [1]
Compared to fingolimod, amiselimod is designed to minimize its activity against the S1P₃ receptor and slow its conversion to the active metabolite, thereby reducing first-dose bradycardia associated with early S1P receptor modulators. [1] Its unique pharmacokinetic characteristics (extremely long half-life and slow accumulation) allow it to be administered once daily without dose titration. [1] This study hypothesizes that, at the expected clinical dose, amiselimod has the potential to treat relapsing-remitting multiple sclerosis and other autoimmune diseases with minimal cardiac effects. [1] |
| Molecular Formula |
C19H31CLF3NO3
|
|---|---|
| Molecular Weight |
413.910
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| Exact Mass |
413.194
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| Elemental Analysis |
C, 55.14; H, 7.55; Cl, 8.56; F, 13.77; N, 3.38; O, 11.60
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| CAS # |
942398-84-7
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| Related CAS # |
942398-84-7 (HCl); 942399-20-4
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| PubChem CID |
67418070
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| Appearance |
White to off-white solid powder
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| LogP |
0
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| Hydrogen Bond Donor Count |
4
|
| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
27
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| Complexity |
376
|
| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl.FC(C1C(OCCCCCCC)=CC=C(CCC(CO)(CO)N)C=1)(F)F
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| InChi Key |
GEDVJGOVRLHFQG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H30F3NO3.ClH/c1-2-3-4-5-6-11-26-17-8-7-15(12-16(17)19(20,21)22)9-10-18(23,13-24)14-25;/h7-8,12,24-25H,2-6,9-11,13-14,23H2,1H3;1H
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| Chemical Name |
2-amino-2-[2-[4-heptoxy-3-(trifluoromethyl)phenyl]ethyl]propane-1,3-diol;hydrochloride
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| Synonyms |
MT-1303; MT1303; MT 1303; Amiselimod Hydrochloride
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~110 mg/mL (~265.8 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (6.64 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.75 mg/mL (6.64 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4160 mL | 12.0799 mL | 24.1598 mL | |
| 5 mM | 0.4832 mL | 2.4160 mL | 4.8320 mL | |
| 10 mM | 0.2416 mL | 1.2080 mL | 2.4160 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02193217 | Completed | Drug: MT-1303-Low Drug: MT-1303-High |
Relapsing-remitting Multiple Sclerosis |
Mitsubishi Tanabe Pharma Corporation |
N/A | Phase 1 |
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