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Ponesimod (formerly known as ACT-128800; ACT128800; Ponvory) is an orally bioavailable and selective agonist of sphingosine-1-phosphate receptor 1 (S1PR1, S1P1) approved in 2021 by FDA to treat relapsing forms of multiple sclerosis. In autoimmune diseases mediated by lymphocytes, it is a novel therapeutic approach.
| Targets |
S1PR1 ( IC50 = 6 nM ); S1PR5 ( IC50 = 142 nM ); S1PR4 ( IC50 = 1956 nM ); S1PR3 ( IC50 = 2068 nM )
Sphingosine-1-phosphate receptor 1 (S1P₁). Ponesimod is a selective, orally active S1P₁ receptor agonist. [1] In a GTPγS binding assay using human recombinant receptors, ponesimod showed an EC₅₀ of 5.7 nM for S1P₁, and greater than 10,000 nM for S1P₂, 105 nM for S1P₃, 1,108 nM for S1P₄, and 59.1 nM for S1P₅. [1] |
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| ln Vitro |
Ponesimod (compound 8bo) acts as a potent, selective, and fully efficacious S1P₁ receptor agonist. In a GTPγS binding assay using membrane preparations of CHO cells expressing human recombinant S1P receptors, ponesimod showed an EC₅₀ of 5.7 nM for S1P₁. In a ³³P-S1P binding assay, ponesimod showed an IC₅₀ of 6.0 nM for S1P₁, >10,000 nM for S1P₂, 68 nM for S1P₃, 1,956 nM for S1P₄, and 142 nM for S1P₅. Ponesimod acts as a partial agonist on S1P₄ (maximal effect 18% of S1P at 10 μM) and S1P₅ (never reaches the efficacy of S1P). [1]
In a GTPγS binding assay using membrane preparations of CHO cells expressing rat S1P₁ and S1P₃ receptors, ponesimod showed EC₅₀ values of 8 nM (rat S1P₁) and 1,455 nM (rat S1P₃). For mouse receptors, EC₅₀ values were 10 nM (mouse S1P₁) and 2,016 nM (mouse S1P₃). [2] In a radioligand binding assay using membranes from CHO cells expressing recombinant human S1P receptors, ponesimod displaced ³³P-S1P with Kᵢ values of 2.2 nM (S1P₁), >10,000 nM (S1P₂), 46.9 nM (S1P₃), 1,519 nM (S1P₄), and 105 nM (S1P₅). [2] Ponesimod stimulates human S1P1-5 uptake, with EC50s of 5.7, >10000, 105, 1108 and 59.1 nM in GTPγS binding assay [2]. Ponesimod stimulates S1P1 reception; for human, relay, and mouse S1P reception, the corresponding EC50 values are 5.7, 1.9, and 1.4 nM [2]. |
| ln Vivo |
In male Wistar rats, oral administration of ponesimod (8bo) at 3 mg/kg achieved maximal reduction of circulating lymphocytes (65-75%). A dose of 100 mg/kg maintained a maximal effect for about 24 hours, and lymphocyte counts recovered completely within less than 36 hours, demonstrating rapid reversibility. [1]
In male Wistar rats, oral administration of ponesimod at 10 mg/kg resulted in a relative reduction in blood lymphocyte counts of -65 ± 4% at 3 hours and -63 ± 3% at 6 hours post-dose. [1] In a rat model of experimental autoimmune encephalomyelitis (EAE), oral administration of ponesimod at 3 or 10 mg/kg once daily for 20 days significantly reduced the clinical score, disease incidence, and central nervous system lymphocyte infiltration. [2] In a rat model of adjuvant-induced arthritis, oral administration of ponesimod at 3 or 10 mg/kg once daily for 18 days dose-dependently reduced paw swelling. [2] In a first-in-human study, single oral doses of ponesimod (8-75 mg) reduced total lymphocyte count in a dose-dependent manner. A maximal mean percentage reduction from baseline of 70.3 ± 2.3% was observed at the 75 mg dose. Lymphocyte counts returned to normal ranges within 96 hours. [3] Ponesimod (30 and 175 mg/kg; once daily, facial, for 8 days) avoids hypersensitivity reactions to sprays that are delayed in type[2]. Ponesimod (30 mg/kg, 3 hours before spraying and 6 hours after adjuvant injection, then 100 mg/kg/day as a food mixture formulation for 18 days) is used in drug formulations to stop adjuvant-induced arthritis[2]. Ponesimod (single wall dose; 0.3-100 mg/kg) Adjacent counts were reduced to 1900/μL after taking ponesimod (100 mg/kg; daily lateral wall gavage for 7 days), and this effect lasted for the full 7 days of the study. Within 48 hours of stopping the perfume, counts went back to baseline levels[2]. |
| Enzyme Assay |
GTPγS Binding Assay: The potency of ponesimod on human, rat, and mouse S1P receptors was assessed using a GTPγS binding assay. Membrane preparations of CHO cells expressing recombinant S1P receptors were incubated with test compound in assay buffer containing 20 mM HEPES (pH 7.4), 100 mM NaCl, 5 mM MgCl₂, 0.1% fatty acid-free BSA, 1 or 3 μM GDP (for S1P₁ or S1P₃, respectively), 2.5% DMSO, and 50 pM [³⁵S]GTPγS. The reaction mixture was incubated for 1 hour at room temperature, then filtered through GF/C plates, washed, and membrane-bound radioactivity was measured. EC₅₀ values were calculated as the concentration inducing 50% of specific binding. [1, 2]
Radioligand Binding Assay: The binding affinity of ponesimod to human S1P receptors was determined using a ³³P-S1P binding assay. Membrane preparations of CHO cells expressing recombinant human S1P receptors were incubated with test compound and 0.1 nM ³³P-S1P in assay buffer (50 mM HEPES, pH 7.5, 5 mM MgCl₂, 0.5% fatty acid-free BSA, and Complete™ protease inhibitor cocktail) for 60-90 minutes at room temperature. Bound and free radioligand were separated by filtration over GF/B plates, and radioactivity was measured by liquid scintillation counting. IC₅₀ values were determined, and Kᵢ values were calculated using the Cheng-Prusoff equation. [2] In assays for GTPηS binding, membrane preparations from cells expressing human, rat, or mouse recombinant S1P receptors are used. Using IC50 Witch, EC50 values were ascertained. As an external maximum and a minimum for the solvent, the maximal response produced by S1P (the percentage effect of maximal response) was used to express the results as an EC50. The geometric mean and geometric standard deviation of the data are expressed as nanomoles of EC50. |
| Animal Protocol |
Rat Lymphocyte Count Study: Male Wistar rats (n=6 per group) received a single oral administration of ponesimod (3, 10, 30, or 100 mg/kg) or vehicle (5% DMSO in 7.5% gelatin in water). Blood was collected before dosing and at 3, 6, 9, 12, 18, and 24 hours post-dose. Total lymphocyte counts were measured using a hematology analyzer. [1]
Rat Experimental Autoimmune Encephalomyelitis (EAE) Model: Female Lewis rats were immunized with guinea pig myelin basic protein in complete Freund's adjuvant. Ponesimod (3 or 10 mg/kg) or vehicle was administered orally once daily for 20 days starting at disease onset (day 11 post-immunization). Clinical signs were scored daily (0-5 scale), and CNS lymphocyte infiltration was assessed by histology and flow cytometry. [2] Rat Adjuvant-Induced Arthritis Model: Female Lewis rats were immunized with heat-inactivated Mycobacterium tuberculosis in mineral oil. Ponesimod (3 or 10 mg/kg) or vehicle was administered orally once daily for 18 days starting at disease onset (day 11 post-immunization). Paw volume was measured using plethysmometry. [2] First-in-Human Study: Healthy male subjects (n=6 per dose group, plus 2 placebo per group) received single oral doses of ponesimod (1, 3, 8, 20, 50, or 75 mg) or placebo under fasted conditions. For the 20 mg dose, a fed state condition (high-calorie breakfast) was also evaluated. Blood samples were collected for pharmacokinetic analysis up to 48 hours (extended to 7 days for the 75 mg dose) and for lymphocyte count measurement. Heart rate, blood pressure, and ECG were monitored. [3] Female BALB/c mice (15-25 g) sensitized with DNFB 30 and 175 mg/kg Gavage (30 mg/kg) 19 and 3 h before sensitization, followed by administration as food admix (175 mg/kg/day) for 8 days |
| ADME/Pharmacokinetics |
Ponesimod (8bo) in male Wistar rats showed a bioavailability of 31% after oral administration (10 mg/kg), with a Cmax of 311 ng/mL at a dose of 10 mg/kg. The half-life (t₁/₂) was 1.4 hours, clearance was 48 mL/min/kg, and Vss was 5.2 L/kg. [1]
In male beagle dogs, ponesimod (8bo) showed a bioavailability of 69% after oral administration (3 mg/kg). The Cmax was 1360 ng/mL at 3 mg/kg, t₁/₂ was approximately 10 hours, and clearance was 25 mL/min/kg. [1] In healthy human subjects, single oral doses of ponesimod (1-75 mg) showed dose-proportional pharmacokinetics. Median tmax ranged from 2.0 to 4.0 hours, and mean terminal t₁/₂ ranged from 21.7 to 33.4 hours. Cmax and AUC₀→∞ increased proportionally with dose (power model slope of 1.02 for both). Intersubject variability (CV%) did not exceed 36%. Food had a minimal effect on ponesimod pharmacokinetics, with fed/fasted ratios of 1.1 (Cmax) and 1.2 (AUC). [3] A two-compartment model with first-order absorption adequately described ponesimod plasma concentration-time profiles. Apparent clearance (CL/F) was 6.7 L/h, apparent volume of central compartment (Vcentral/F) was 304 L, and absorption rate constant (kₐ) was 0.67 h⁻¹. [3] |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation Although peonsimod has a high binding rate in maternal plasma and is unlikely to enter breast milk in large quantities, it still poses potential toxicity to breastfed infants. Since no studies have been published on the use of peonsimod during lactation, experts generally recommend avoiding the use of fingolimod, a drug closely related to it, during lactation, especially when breastfeeding newborns or premature infants. However, the manufacturer's instructions do not recommend contraindications to peonsimod during lactation. ◉ Effects on Breastfed Infants No published information found as of the revision date. ◉ Effects on Lactation and Breast Milk No published information found as of the revision date. |
| References |
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| Additional Infomation |
Ponesimod is a sphingosine-1-phosphate receptor modulator. The mechanism of action of ponesimod is as a sphingosine-1-phosphate receptor modulator.
See also: Ponesimod (note moved to). |
| Molecular Formula |
C23H25CLN2O4S
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|---|---|
| Molecular Weight |
460.97
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| Exact Mass |
460.122
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| Elemental Analysis |
C, 59.93; H, 5.47; Cl, 7.69; N, 6.08; O, 13.88; S, 6.95
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| CAS # |
854107-55-4
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| Related CAS # |
Ponesimod-d4; Ponesimod-d7
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| PubChem CID |
11363176
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| Appearance |
Off-white to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
658.0±65.0 °C at 760 mmHg
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| Flash Point |
351.7±34.3 °C
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| Vapour Pressure |
0.0±2.1 mmHg at 25°C
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| Index of Refraction |
1.619
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| LogP |
5.08
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
31
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| Complexity |
674
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| Defined Atom Stereocenter Count |
1
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| SMILES |
N(=C1/S/C(=C\C2C=CC(OC[C@H](O)CO)=C(Cl)C=2)/C(=O)N/1C1C=CC=CC=1C)/CCC
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| InChi Key |
LPAUOXUZGSBGDU-ULCCENQXSA-N
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| InChi Code |
InChI=1S/C23H25ClN2O4S/c1-3-10-25-23-26(19-7-5-4-6-15(19)2)22(29)21(31-23)12-16-8-9-20(18(24)11-16)30-14-17(28)13-27/h4-9,11-12,17,27-28H,3,10,13-14H2,1-2H3/b21-12-,25-23?/t17-/m1/s1
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| Chemical Name |
(5Z)-5-[[3-chloro-4-[(2R)-2,3-dihydroxypropoxy]phenyl]methylidene]-3-(2-methylphenyl)-2-propylimino-1,3-thiazolidin-4-one
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| Synonyms |
ACT-128800; Ponesimod; ACT 128800; 854107-55-4; ACT-128,800; Ponvory; 5G7AKV2MKP; Ponvory; ACT128800
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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 |
| 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: ~92 mg/mL (~199.6 mM)
Ethanol: ~92 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.42 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.42 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 25.0 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 | 2.1693 mL | 10.8467 mL | 21.6934 mL | |
| 5 mM | 0.4339 mL | 2.1693 mL | 4.3387 mL | |
| 10 mM | 0.2169 mL | 1.0847 mL | 2.1693 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.
ACT-128800 in Patients With Moderate to Severe Chronic Plaque Psoriasis
CTID: NCT01208090
Phase: Phase 2 Status: Completed
Date: 2023-01-04
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