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Melphalan Flufenamide

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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

Melphalan Flufenamide

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 Formula	C₂₄H₃₀Cl₂FN₃O₃
Molecular Weight	498.4 g/mol
XLogP3	3.2
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	14
Exact Mass	497.1648254 g/mol
Monoisotopic Mass	497.1648254 g/mol
Topological Polar Surface Area	84.7 Å²
Heavy Atom Count	33
Formal Charge	0
Complexity	579
Isotope Atom Count	0
Defined Atom Stereocenter Count	2
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

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 C_max of 432 ng/mL, with a T_max 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.

Drugs in Development