Pidotimod Property

Melting point:

194-198°C (dec.)

alpha 

D25 -150° (c = 2 in 5N HCl)

Boiling point:

663.0±55.0 °C(Predicted)

Density 

1.53

storage temp. 

Keep in dark place,Sealed in dry,2-8°C

solubility 

DMSO (Slightly, Heated), Methanol (Slightly, Heated), 5N HCl (Slightly)

pka

3.03(at 25℃)

form 

powder

color 

white to beige

optical activity

[α]/D -135 to -155°, c = 1 in 6 M HCl

Merck 

14,7419

InChI

InChI=1S/C9H12N2O4S/c12-7-2-1-5(10-7)8(13)11-4-16-3-6(11)9(14)15/h5-6H,1-4H2,(H,10,12)(H,14,15)/t5-,6-/m0/s1

InChIKey

UUTKICFRNVKFRG-WDSKDSINSA-N

SMILES

S1C[C@@H](C(O)=O)N(C([C@@H]2CCC(=O)N2)=O)C1

CAS DataBase Reference

121808-62-6(CAS DataBase Reference)

Safety

RTECS 

XJ5426675

HS Code 

2934.10.9000

Toxicity

LD50 in mice and rats (mg/kg): >4000 i.v.; >4000 i.m.; >8000 i.p.; >8000 orally (Coppi)

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H302Harmful if swallowed

H315Causes skin irritation

H319Causes serious eye irritation

H335May cause respiratory irritation

Precautionary statements

P261Avoid breathing dust/fume/gas/mist/vapours/spray.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

Pidotimod Chemical Properties,Usage,Production

Immunomodulator

Pidotimod, chemical name (4R)-3-(5-oxo-L-prolyl)-1,3-thiazolidine-4-carboxylic acid, is a representative of synthetic immunostimulants, its structure is similar with dipeptide. Pidotimod has anti-toxicity, anti-oxidation, anti-irritation, anti-infectivity properties etc.; it can promote both innate immunity responses and adaptive immunity responses. Clinically it is mainly used to treat children with recurrent respiratory infections, chronic bronchitis, recurrent urinary tract infections, other chronic diseases caused by machine body with low immune function and to reduce the recurrence of tumor. Pidotimod can be rapidly absorbed, excreted with no accumulation in the body, with good tolerance and with no restriction on the age of patients.
Pidotimod was originally developed by Poli Industria Chimica S.p.A, Italy. It was listed in 1993 and put into clinical practice. In 2003 our country imported pidotimod oral solution. At present, there are few approved raw material manufacturers to produce pidotimod.
Immunomodulators are drugs that regulate the function of the immune system. Studies have found that some immunomodulators do not have effect on the normal immune system, but can enhance the function of the immune system and regulate the immune responses. Pidotimod is a synthetic immunosuppressive agent with dipeptide like structure, and promote both innate and adaptive immunity of the machine body. On the one hand, pidotimod can block phagocytosis of cyclophosphamide on phagocytic cells (monocyte/macrophage, neutrophils, and etc.) and the suppression effect of cyclophosphamide on the proliferation of lymphocyte, enhance the phagocytosis of phagocytic cells, increase the cell chemotaxis, enhance the sensitivity of B cells, produce more antibodies to against foreign bodies, especially increase the production of protective secretory IgA; activate the natural killer cell (NK) to regulate the balance of T cells in the immune system; stimulate the proliferation of B/T lymphocyte. On the other hand, by stimulating the production of cytokines, interleukin-2 and interferon-y, pidotimod can further promote the phagocytosis of phagocytic cells, the activation of lymphocyte and cellular immune response; correct the imbalance of CD4+/CD8+ ratio in pathological condition to regulate the body’s immune system to the steady state under normal physiological condition. Furthermore, pidotimod can enhance deficitary feedback mechanism between the hypothalamic-pituitary-adrenal (HPA) axis and interleukin-1 (IL-1). Further studies have shown that: pidotimod could reconstitute the cellularity of the pritoneum and of the spleens of mice immunodepressed by mPDN. Pidotimod stimulate production of cytokines and other effects, the mutual coordination and restraint of vary cytokines and immune cells to adjust the immune system disorder in pathological condition to the normal body immunity.

Figure 1: Function mechanism of pidotimod
①: Pidotimod activates natural killer cells.
②: Pidotimod can correct the imbalance of CD+4/Cd+8 ratio.
③: Pidotimod can increase the activity of T cells and enhance the ability of T cells to eliminate virus.
④: Pidotimod can increase the level of IL/2 and IFN-γ in the immune response, enhance the body immunity.   
⑤: Pidotimod can promote the activity of macrophage.
⑥: Pidotimod can quickly increase the chemotaxis of neutrophils.

Physical and Chemical Properties

The chemical name of pidotimod is: (4R)-3-(5-oxo-L-prolyl)-1,3-thiazolidine-4-carboxylic acid. Its formula is C9H13N2O4S, molecular mass is 244.26 g/mol. It is a white odorless crystalline powder, soluble in water, almost insoluble in chloroform. Its melting point is: 192-198°C.

Synthesis Method

First L-cysteine (1) was reacted with formaldehyde to give L-thiazolidine-4-carboxylic acid (2). L-pyroglutamic acid (3) was reacted with pentachlorophenol in solvent N,N-dimethylformamide (DMF) and with the presence of a condensing agent dicyclohexylcarbodiimide (DCC) to give  L-pyroglutamic acid pentachlorophenyl ester (4). The compound (2) reacted with compound (4) in solvent DMF and with deacid agent triethylamine to give pidotimod after dehydration condensation.

Figure 2: Synthesis route of pidotimod.

Clinical Applications

Applicable to patients with low immune function. It can be used to treat recurrent respiratory tract infection; infection in ear, nose, and throat; as adjuvant therapy for urogenital system infection; to treat virus infection, malignancies, and other chronic diseases.

Pharmacokinetics

This product can be taken orally, the bioavailability is 35%. Food intake might affect the absorbance of this drug. 2 hours after oral administration the peak of pidotimod concentration in plasma is reached. The plasma protein binding rate of pidotimod is very low and it is barely metabolized in body, and almost excreted as unmodified drug in the urine. The half life of pidotimod is 4 hours.
The physical and chemical properties, synthesis method, clinical applications, adverse reactions etc. are edited by the editor Dongfang of Chemicalbook. (2016-01-13)

Adverse Reactions

Occasionally observed headaches, dizziness, nausea, vomiting, diarrhea, rash etc.
Toboos: Allergic to this product disabled.

Precautions

• Highly susceptible individuals with caution.
• There is no information about this drug concerning pregnant and lactating women, thus, it is not suitable for pregnant and lactating women.
• Strictly abide by the usage and dosage in children. There are no reports on the application for children under 2 years old.
• There are no systematic clinical data on elderly patients.
• There are no reports on the overdose of this drug. In case of overdose, conventional methods could be used, such as vomiting, cathartic, infusion, and other drugs to promote excretion of excessive drug.

Drug Interactions

Avoid taking this drug when taking meals. It can be taken either before meals or 2 hours after the meal.

Description

Pidotimod, a dipeptide immunomodulating agent, has been introduced as immunostimulant therapy in patients with cell-mediated immunosuppression during respiratory or urinary tract infections. Its mode of action on the immune system is by activation of T-lymphocytes via interleukin (IL)-2 stimulation and macrophages via activation of superoxide dismutase and chemotaxis. In mice, treatment with pidotimod causes significant increase in the natural killer cell activity that may play an important role in immunosurveillance against tumors and in physiological homeostasis. Pidotimod can reverse the immunosuppression caused by surgical stress and has antiinflammatory, antioxidant, and antiaging properties. It has also been reported to provide protection from bacterial infections in mice.

Chemical Properties

White Solid

Originator

Poli (Italy)

Uses

Immunostimulant used in patients with cell-mediated immunodepression.

Uses

immune stimulant

Definition

ChEBI: (4R)-3-[oxo-[(2S)-5-oxo-2-pyrrolidinyl]methyl]-4-thiazolidinecarboxylic acid is a peptide.

brand name

Polimod; Pigitil; Axil; Onaka