N-Acetylmuramyl-alanyl-isoglutaminyl-alanyl-sn-glycero-3-phosphoethano lamine Chemical Properties

Density 

1.152

storage temp. 

-20°C

solubility 

water: soluble2mg/mL, clear (warmed)

form 

powder

pka

1.39±0.50(Predicted)

color 

white to beige

InChIKey

ZVLWUMPAHCEZAW-HYGHKABSNA-N

CAS DataBase Reference

83461-56-7

Safety Information

WGK Germany 

3

N-Acetylmuramyl-alanyl-isoglutaminyl-alanyl-sn-glycero-3-phosphoethano lamine Usage And Synthesis

Uses

Osteosarcoma.

Uses

Mifamurtide may be used in immunological and cancer-related cell signaling studies.

Biochem/physiol Actions

Mifamurtide is an immunomodulator and regulates the activation of monocytes and macrophages. Mifamurtide upregulates the secretion of pro-inflammatory cytokines such as TNF-α, IL-1, IL-8, nitric oxide and prostaglandins E2 and D2. It has anti-tumor effects in children and young adults with high-grade osteosarcoma.

Mechanism of action

Being a phospholipid, mifamurtide accumulates in the lipid bilayer of the liposomes upon infusion. After application of the liposomal infusion, the drug is cleared from the plasma within minutes. However, it is concentrated in lung, liver, spleen, nasopharynx and thyroid, and the terminal half-life is 18 hours, which is longer than the natural substance.

Clinical Use

Mifamurtide is an anticancer agent for the treatment of osteosarcoma, the most common primary malignancy of bone tissue mainly affecting children and adolescents. The drug was invented by Ciba-Geigy (now Novartis) in the early 1980s and the agent was subsequently licensed to Jenner Biotherapies in the 1990s. IDM Pharma bought the rights to the drug from Jenner in April 2003.In March 2009, mifamurtide was approved in the 27 European Union member states plus Iceland, Liechtenstein and Norway via a centralized marketing authorization. After the approval, IDM Pharma was acquired by Takeda, which began launching mifamurtide, as Mepact ®, in February 2010. Mifamurtide, a fully synthetic lipophilic derivative of muramyl dipeptide (MDP), is muramyl tripeptide phosphatidylethanolamine (MTP-PE), which is formulated as a liposomal infusion.

Synthesis

Two synthetic routes have been reported, and the scheme describes the more process-amenable route. Commercially available 1,2-dipalmitoyl-snglycero- 3-phosphoethanolamine (110) was coupled with N-Boc-L-alanine (111) by means of Nhydroxysuccinimide (112), DCC in DMF to give amide 113, which was followed by hydrogenolysis of the CBZ group to give the corresponding L-alanyl-phosphoric acid 114. Next, commercially available N-acetylmuramoyl-L-alanyl-D-isoglutamine (115) was subjected to hydroxybenzotriazole (HOBT) and DIC in DMF to provide the corresponding succinimide ester 116 which was condensed with compound 114 to provide mifamurtide (IX). No yields were provided for these transformations.

Drug interactions

Potentially hazardous interactions with other drugs
Analgesics: avoid with high dose NSAIDs.
Ciclosporin: avoid concomitant use.
Corticosteroids: avoid concomitant use.
Tacrolimus: avoid concomitant use.

Metabolism

The cells of the reticuloendothelial system clear mifamurtide liposomes by phagocytosis.

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