Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C24H30Cl2FN3O3 |
Molecular Weight | 498.4185 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 2 / 2 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CCOC(=O)[C@]([H])(Cc1ccc(cc1)F)N=C([C@]([H])(Cc2ccc(cc2)N(CCCl)CCCl)N)O
InChI
InChIKey=YQZNKYXGZSVEHI-VXKWHMMOSA-N
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
Molecular Formula | C24H30Cl2FN3O3 |
Molecular Weight | 498.4185 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 2 / 2 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
Melphalan flufenamide ethyl ester (melflufen, previously denoted J1) is a peptidase-potentiated dipeptide prodrug of alkylating agent melphalan. Melflufen readily penetrates membranes and an equilibrium is rapidly achieved, followed by enzymatic cleavage in aminopeptidase positive cells, which results in trapping of less lipophilic metabolites. This targeting effect results in very high intracellular concentrations of its metabolite melphalan and subsequent apoptotic cell death. This results in a potency increase (melflufen vs melphalan) ranging from 10- to several 100-fold in different in vitro models. Melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome melphalan-resistance in multiple myeloma cells. Melflufen has been granted orphan drug designation for the treatment of multiple myeloma.
Originator
Approval Year
PubMed
Title | Date | PubMed |
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In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells. | 2013 Jun 1 |
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In vitro and in vivo activity of melflufen (J1)in lymphoma. | 2016 Apr 4 |
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A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. | 2016 Aug |
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In vitro and in vivo anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia. | 2017 Jan 24 |
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Melflufen - a peptidase-potentiated alkylating agent in clinical trials. | 2017 Sep 12 |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT03151811
Phase 3 clinical study (OCEAN, OP-103). Melflufen 40 mg i.v. on Day 1 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle.
Route of Administration:
Intravenous
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/27044263
Melflufen showed activity with cytotoxic IC50-values in the submicromolar range (0.011-0.92 μM) in the cell lines. In the primary cultures melflufen yielded slightly lower IC50-values (2.7 nM to 0.55 μM). Treated cell lines exhibited a clear accumulation in the G2/M-phase of the cell cycle.
Substance Class |
Chemical
Created
by
admin
on
Edited
Fri Jun 25 23:17:09 UTC 2021
by
admin
on
Fri Jun 25 23:17:09 UTC 2021
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Record UNII |
F70C5K4786
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Record Status |
Validated (UNII)
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Record Version |
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NCI_THESAURUS |
C697
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NCI_THESAURUS |
C1742
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EU-Orphan Drug |
EU/3/15/1463
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9935639
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F70C5K4786
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C107680
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380449-51-4
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METABOLITE -> PARENT |
Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Volume of Distribution | PHARMACOKINETIC |
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Biological Half-life | PHARMACOKINETIC |
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Tmax | PHARMACOKINETIC |
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Melphalan flufenamide peak plasma concentrations were reached during the 30-minute infusion. PHARMACOKINETIC |
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