Ponesimod Chemical Properties

Boiling point:

658.0±65.0 °C(Predicted)

Density 

1.30±0.1 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

Soluble in DMSO

form 

A crystalline solid

pka

13.38±0.20(Predicted)

color 

Off-white to yellow

InChIKey

LPAUOXUZGSBGDU-STDDISTJSA-N

SMILES

S1/C(=C\C2=CC=C(OC[C@H](O)CO)C(Cl)=C2)/C(=O)N(C2=CC=CC=C2C)/C/1=N/CCC

Safety Information

WGK Germany 

WGK 3

Storage Class

6.1C - Combustible acute toxic Cat.3
toxic compounds or compounds which causing chronic effects

Hazard Classifications

Acute Tox. 4 Oral
Repr. 1B

Ponesimod Usage And Synthesis

Description

Ponesimod is an oral drug developed by Johnson & Johnson's Janssen Pharmaceuticals unit and approved in 2021 for the treatment of relapsing multiple sclerosis (MS). MS is a chronic inflammatory disease that affects the central nervous system, resulting in neurological dysfunction and disability.

Uses

Ponesimod is an orally active sphingosine-1-phosphate receptor agonist. It protects against lymphocyte-mediated tissue inflammation.

brand name

Ponvory

Biological Activity

ec50: 5.7 nmponesimod is a sphingosine-1-phosphate receptor 1 (s1p1) modulator.lymphocyte exit from lymph nodes and its recirculation into blood is reported to be controlled by s1p. the cellular receptor mediating lymphocyte exit is one of five s1p receptors, s1p1. thus, the nonselective agonists for s1p1 lead to blood lymphocyte count reduction.

Mechanism of action

Ponesimod is a selective sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) agonist. S1P is an intracellular signalling molecule involved in a variety of biological processes including cell migration and survival.Ponesimod works by binding to the S1P1 receptor, leading to internalisation of the receptor. thereby inhibiting the efflux of lymphocytes from the lymph nodes. This action reduces the number of lymphocytes in the blood and limits their ability to reach sites of inflammation, helping to slow the progression of multiple sclerosis.

Synthesis

Ponesimod was synthesised using a three-component coupling of isothiocyanate 16.1, n-propylamine and 2-bromoacetylbromide 16.2 to construct the thiazolidin-4-one parent nucleus 16.3.The regioselectivity of this cyclisation was heavily dependent on the haloacetic acid derivative chosen; in this case, 2-bromoacetylbromide 16.2 showed a high regioselectivity for the desired 16.3 (ratio 41:1, 16.3: 16.4) showed high regioselectivity, in contrast to the lower selectivity of methyl 2-bromoacetate (ratio 1:10, 16.3:16.4). Subsequent hydroxyaldol condensation (aldol-type condensation) with aldehyde 16.5 yielded phenol 16.6, and overall high yields were obtained from the starting isothiocyanate 16.1. The final step involved the attachment of chiral chloropropanediol 16.7 to phenol 16.6 via the SN2 mechanism in the presence of a base, resulting in the synthesis of Ponesimod (16).

in vitro

previous study found that ponesimod could activate s1p1-mediated signal transduction with high potency. moreover, relative to the potency for s1p, the potency of ponesimod at human recombinant receptors was 4.4-fold higher for s1p1 and 150-fold lower for human s1p3. thus, ponesimod was 650-fold more selective for human s1p1 over s1p3 than the endogeneous ligand [1].

in vivo

animal study showed that the oral administration of ponesimod to rats resulted in a dose-dependent decrease of blood lymphocyte count, and the blood lymphocyte count returned to baseline within 48 h after discontinuation of ponesimod treatment. in addition, ponesimod prevented inflammatory cell accumulation, edema formation, as well as cytokine release in the skin of mice with delayed-type hypersensitivity. furthermore, in rats with adjuvant-induced arthritis, ponesimod could also prevent the increase in paw volume and joint inflammation [2].

IC 50

S1PR1: 6 nM (IC₅₀); S1PR5: 142 nM (IC₅₀); S1PR4: 1956 nM (IC₅₀); S1PR3: 2068 nM (IC₅₀)

References

[1] piali l, froidevaux s, hess p, nayler o, bolli mh, schlosser e, kohl c, steiner b, clozel m. the selective sphingosine 1-phosphate receptor 1 agonist ponesimod protects against lymphocyte-mediated tissue inflammation. j pharmacol exp ther. 2011 may;337(2):547-56.
[2] d'ambrosio d, freedman ms, prinz j. ponesimod, a selective s1p1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases. ther adv chronic dis. 2016 jan;7(1):18-33.