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General Description:

Ponesimod, identified by CAS number 854107-55-4, is a notable compound with significant therapeutic applications. Ponesimod is a selective sphingosine 1-phosphate receptor 1 modulator indicated in the treatment of relapsing forms of multiple sclerosis in adults. Ponesimod was developed out of a need for a more selective modulator of sphingosine 1-phosphate receptor 1 than . Fingolimod's activity at sphingosine 1-phosphate receptor 3 was suspected to be responsible for a portion of it's adverse effects, and so more selective modulators were developed. Ponesimod was granted FDA approval on 18 March 2021.

Indications:

This drug is primarily indicated for: Ponesimod is indicated to treat adults with relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Ponesimod undergoes metabolic processing primarily in: Ponesimod can be sulfated to the M5 metabolite, oxidized to an undefined M27 metabolite, reduced to the M6 metabolite, dealkylated to the M32 metabolite, or oxidized and hydrolyzed to the M13 metabolite. Ponesimod can also be oxidized by CYP2J2, CYP3A4, CYP3A5, CYP4F3A, and CYP4F12 to the M12 metabolite. The undefined M27 metabolite can be glucuronidated by UGT1A1 and UGT 2B7 to the M38, M39, and M40 metabolites. The M12 metabolite is either dealkylated to the M32 metabolite or oxidized and hydrolyzed to M13. M13 is dealkylated to M32, which is reduced and oxidized to M48. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Ponesimod are crucial for its therapeutic efficacy: A 10mg oral dose of ponesimod is 84% bioavailable. Ponesimod reaches a C_max of 109 ng/mL, with a T_max of 4.0 hours, and an AUC of 3872 h\*ng/mL. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Ponesimod is an important consideration for its dosing schedule: Ponesimod has an elimination half life of 33 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Ponesimod exhibits a strong affinity for binding with plasma proteins: Ponesimod is >99% protein bound in plasma. Though the proteins it binds to have not been identified in literature. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Ponesimod from the body primarily occurs through: 57.3-79.6% of a radiolabelled oral dose is recovered in the feces, with 16-26% as the unmetabolized parent compound and 22% as the M12 metabolite. 10.3-18.4% of an oral dose is eliminated in the urine. 0.6-1.9% of a radiolabelled dose was recovered as expired CO₂. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Ponesimod is distributed throughout the body with a volume of distribution of: The volume of distribution of ponesimod at steady state is 160 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Ponesimod is a critical factor in determining its safe and effective dosage: The clearance of ponesimod is 3.8 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Ponesimod exerts its therapeutic effects through: Ponesimod is a sphingosine 1-phosphate receptor 1 modulator indicated to treat adults with relapsing forms of multiple sclerosis. It has a long duration of action as it is given once daily. Patients should be counselled about the risk of infections, bradyarrhythmia, atrioventricular conduction delays, decreased respiratory function, liver injury, increased blood pressure, cutaneous malignancies, fetal harm, and macular edema. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Ponesimod functions by: The sphingosine 1-phosphate receptor 1 (S1P1R) is expressed on the surface of lymphocytes and detects sphingosine 1-phosphate (S1P) at nanomolar concentrations. S1P is a metabolite of the cell membrane component, sphingomyelin. As sphingomyelin degrades, lymphocytes respond to agonism of S1P1R by concentration gradients of S1P. Lymphocytes leave the lymphoid organs in response to higher concentrations of S1P in blood and lymph. Ponesimod modulates this response by stimulating and internalizing S1P1R on lymphocytes, effectively blinding them to concentration gradients of S1P, reducing the number of lymphocytes in blood. Ponesimod is roughly 650 times more selective for S1P1R than S1P. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Ponesimod belongs to the class of organic compounds known as phenol ethers. These are aromatic compounds containing an ether group substituted with a benzene ring, classified under the direct parent group Phenol ethers. This compound is a part of the Organic compounds, falling under the Benzenoids superclass, and categorized within the Phenol ethers class, specifically within the None subclass.

Categories:

Ponesimod is categorized under the following therapeutic classes: Antineoplastic and Immunomodulating Agents, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Substrates, Cytochrome P-450 Substrates, Immunologic Factors, Immunomodulatory Agents, Immunosuppressive Agents, Receptors, Lysosphingolipid, antagonists & inhibitors, Selective Immunosuppressants, Sphingosine 1 Phosphate Receptor Modulators, Sphingosine 1-phosphate Receptor Modulator, Sulfur Compounds, UGT1A1 Substrates, UGT2B7 substrates. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Ponesimod include:

• Water Solubility: Insoluble