Please Wait
Applying Filters...
menu
    • menu
    DRL offers a portfolio of products & services, including APIs, CMO services, generics, biosimilars & differentiated formulations.

    Virtual Booth

    Contact Supplier

    Valsynthese, part of the SSE Group, is a CDMO focused on highly energetic and highly hazardous chemistry.

    Virtual Booth

    Contact Supplier

    xyz-pharma-m-2024-10-07

    Virtual Booth

    Contact Supplier

    With Fermion, start the journey of your innovative API.

    Virtual Booth

    Contact Supplier

    Bloomage is a one-stop source for CEP Sodium Hyaluronate and Hyaluronic Acid// FDA-inspected & GMP-certified.

    Virtual Booth

    Contact Supplier

    xyz-pharma-m-2024-10-07

    Virtual Booth

    Contact Supplier

    Menu

    Melphalan Flufenamide

    DEVELOPMENTS

    DIGITAL CONTENT

    PharmaCompass
    Xls

    Filters

    clear-filterReset all filters
    2D Structure
    Also known as: Melflufen, Prodrug j 1, Prodrug j-1, J 1 (prodrug), J-1 (prodrug), 380449-51-4
    Molecular Formula
    C24H30Cl2FN3O3
    Molecular Weight
    498.4  g/mol
    InChI Key
    YQZNKYXGZSVEHI-VXKWHMMOSA-N
    FDA UNII
    F70C5K4786
    Melphalan Flufenamide is a peptide-drug conjugate composed of a peptide conjugated, via an aminopeptidase-targeting linkage, to the alkylating agent melphalan, with potential antineoplastic and anti-angiogenic activities. Upon administration, the highly lipophilic melphalan flufenamide penetrates cell membranes and enters cells. In aminopeptidase-positive tumor cells, melphalan flufenamide is hydrolyzed by peptidases to release the hydrophilic alkylating agent melphalan. This results in the specific release and accumulation of melphalan in aminopeptidase-positive tumor cells. Melphalan alkylates DNA at the N7 position of guanine residues and induces DNA intra- and inter-strand cross-linkages. This results in the inhibition of DNA and RNA synthesis and the induction of apoptosis, thereby inhibiting tumor cell proliferation. Peptidases are overexpressed by certain cancer cells. The administration of melphalan flufenamide allows for enhanced efficacy and reduced toxicity compared to melphalan.
    Melphalan flufenamide is an Alkylating Drug. The mechanism of action of melphalan flufenamide is as an Alkylating Activity.
    1 2D Structure

    2D Structure

    2 Identification
    2.1 Computed Descriptors
    2.1.1 IUPAC Name
    ethyl (2S)-2-[[(2S)-2-amino-3-[4-[bis(2-chloroethyl)amino]phenyl]propanoyl]amino]-3-(4-fluorophenyl)propanoate
    2.1.2 InChI
    InChI=1S/C24H30Cl2FN3O3/c1-2-33-24(32)22(16-18-3-7-19(27)8-4-18)29-23(31)21(28)15-17-5-9-20(10-6-17)30(13-11-25)14-12-26/h3-10,21-22H,2,11-16,28H2,1H3,(H,29,31)/t21-,22-/m0/s1
    2.1.3 InChI Key
    YQZNKYXGZSVEHI-VXKWHMMOSA-N
    2.1.4 Canonical SMILES
    CCOC(=O)C(CC1=CC=C(C=C1)F)NC(=O)C(CC2=CC=C(C=C2)N(CCCl)CCCl)N
    2.1.5 Isomeric SMILES
    CCOC(=O)[C@H](CC1=CC=C(C=C1)F)NC(=O)[C@H](CC2=CC=C(C=C2)N(CCCl)CCCl)N
    2.2 Other Identifiers
    2.2.1 UNII
    F70C5K4786
    2.3 Synonyms
    2.3.1 MeSH Synonyms

    1. Melflufen

    2. Melphalan-flufenamide

    3. Pepaxto

    2.3.2 Depositor-Supplied Synonyms

    1. Melflufen

    2. Prodrug J 1

    3. Prodrug J-1

    4. J 1 (prodrug)

    5. J-1 (prodrug)

    6. 380449-51-4

    7. 380449-51-4 (free Base)

    8. F70c5k4786

    9. J-1

    10. L-phenylalanine, 4-(bis(2-chloroethyl)amino)-l-phenylalanyl-4-fluoro-, Ethyl Ester

    11. Ethyl (2s)-2-((2s)-2-amino-3-(4-(bis(2-chloroethyl)amino)phenyl)propanamido)-3-(4-fluorophenyl)propanoate

    12. J1

    13. Mff

    14. Ethyl (2s)-2-[[(2s)-2-amino-3-[4-[bis(2-chloroethyl)amino]phenyl]propanoyl]amino]-3-(4-fluorophenyl)propanoate

    15. Ethyl (s)-2-((s)-2-amino-3-(4-(bis(2-chloroethyl)amino)phenyl)propanamido)-3-(4-fluorophenyl)propanoate

    16. Melphalan Flufenamide [inn]

    17. Unii-f70c5k4786

    18. Chembl4303060

    19. Schembl18239898

    20. Gtpl11605

    21. Dtxsid40191461

    22. Glxc-25713

    23. Melphalan Flufenamide (usan/inn)

    24. Melphalan Flufenamide [usan:inn]

    25. Who 9493

    26. Melphalan Flufenamide [usan]

    27. Melphalan Flufenamide [who-dd]

    28. J 1

    29. Hy-105019

    30. Cs-0024709

    31. D11865

    32. Q27277739

    2.4 Create Date
    2006-10-25
    3 Chemical and Physical Properties
    Molecular Weight 498.4 g/mol
    Molecular Formula C24H30Cl2FN3O3
    XLogP33.2
    Hydrogen Bond Donor Count2
    Hydrogen Bond Acceptor Count6
    Rotatable Bond Count14
    Exact Mass497.1648254 g/mol
    Monoisotopic Mass497.1648254 g/mol
    Topological Polar Surface Area84.7 Ų
    Heavy Atom Count33
    Formal Charge0
    Complexity579
    Isotope Atom Count0
    Defined Atom Stereocenter Count2
    Undefined Atom Stereocenter Count0
    Defined Bond Stereocenter Count0
    Undefined Bond Stereocenter Count0
    Covalently Bonded Unit Count1
    4 Drug and Medication Information
    4.1 Drug Indication

    Melphalan flufenamide is indicated in combination with [dexamethasone] to treat adults with relapsed or refractory multiple myeloma who have received 4 therapies and are refractory to at least one proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody. The FDA has withdrawn the drug from the market for this indication following phase 3 trial data showing decreased overall survival.

    Pepaxti is indicated, in combination with dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least three prior lines of therapies, whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one anti-CD38 monoclonal antibody, and who have demonstrated disease progression on or after the last therapy. For patients with a prior autologous stem cell transplantation, the time to progression should be at least 3 years from transplantation (see section 4. 4).

    5 Pharmacology and Biochemistry
    5.1 Pharmacology

    Melphalan flufenamide is an alkylating agent indicated to treat relapsed or refractory multiple myeloma in Melphalan flufenamide has a long duration of action as it is given every 28 days. Patients should be counselled regarding risks of thrombocytopenia, neutropenia, anemia, infections, secondary malignancies, embryo-fetal toxicity.

    5.2 FDA Pharmacological Classification
    5.2.1 Active Moiety
    MELPHALAN FLUFENAMIDE
    5.2.2 FDA UNII
    F70C5K4786
    5.2.3 Pharmacological Classes
    Established Pharmacologic Class [EPC] - Alkylating Drug
    5.3 ATC Code

    L01AA10

    L - Antineoplastic and immunomodulating agents

    L01 - Antineoplastic agents

    L01A - Alkylating agents

    L01AA - Nitrogen mustard analogues

    L01AA10 - Melphalan flufenamide

    5.4 Absorption, Distribution and Excretion

    Absorption

    For a 40 mg intravenous infusion, the active metabolite reaches a Cmax of 432 ng/mL, with a Tmax of 4-15 minutes, and an AUC of 3143 h\*g/mL.

    Route of Elimination

    Data regarding the route of elimination of melphalan flufenamide are not readily available. Free melphalan undergoes rapid and spontaneous decomposition, complicating studies on the route of elimination. However, it is expected to be mainly renally excreted.

    Volume of Distribution

    The mean volume of distribution of melphalan flufenamide is 35 L and of melphalan is 76 L.

    Clearance

    The mean clearance of melphalan flufenamide is 692 L/h and of melphalan is 23 L/h.

    5.5 Metabolism/Metabolites

    Melphalan flufenamide is metabolised to desethyl-melphalan and melphalan. Melphalan is spontaneously hydrolyzed to monohydroxy-melphalan and dihydroxy-melphalan.

    5.6 Biological Half-Life

    The mean elimination half life of melphalan flufenamide is 2.1 minutes and of melphalan is 70 minutes.

    5.7 Mechanism of Action

    Melphalan flufenamide is a more lipophilic prodrug of melphalan, which allows it to be more readily uptaken by cells. It is likely taken up into malignant cells by passive diffusion, where it is hydrolyzed by aminopeptidase N. The expression of aminopeptidases, along with other hydrolytic enzymes, is upregulated in many malignant cells, making the hydrolysis reaction to melphalan more favourable in a malignant cell. Increased concentrations of free melphalan in malignant cells leads to rapid irreversible DNA damage and apoptosis, reducing the potential for the development of resistance. Free melphalan is an nitrogen mustard derivative alkylating agent. Melphalan attaches alkyl groups to the N-7 position of guanine and N-3 position of adenine, leading to the formation of monoadducts, and DNA fragmenting when repair enzymes attempt to correct the error. It can also cause DNA cross-linking from the N-7 position of one guanine to the N-7 position of another, preventing DNA strands from separating for synthesis or transcription. Finally, melphalan can induce a number of different mutations. While melphalan induces phosphorylation of the DNA damage marker -H2AX in melphalan sensitive cells at 6 hours, melphalan flufenamide induces -H2AX at 2 hours. Melphalan flufenamide is also able to induce -H2AX in melphalan-resistant cells.