MELPHALAN FLUFENAMIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C24H30Cl2FN3O3
Molecular Weight	498.418
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CCOC(=O)[C@H](CC1=CC=C(F)C=C1)NC(=O)[C@@H](N)CC2=CC=C(C=C2)N(CCCl)CCCl

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

HIDE SMILES / InChI

Molecular Formula	C24H30Cl2FN3O3
Molecular Weight	498.418
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Melphalan, also known as L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin, is a phenylalanine derivative of nitrogen mustard. Melphalan is a bifunctional alkylating agent which produces a number of DNA adducts with the DNA interstrand crosslink (ICL) considered to be the critical cytotoxic lesion. Melphalan is used to treat different cancers including myeloma, melanoma and ovarian cancer.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA 282	Crosslinking Agent 83		0.078 µM [IC50]
DNA 282	Crosslinking Agent 83

Conditions

Condition	Modality	Highest Phase	Product
Multiple myeloma 159	Palliative	Approved 8,583	ALKERAN
Epithelial carcinoma of the ovary 4	Palliative	Approved 8,583	ALKERAN
Relapsed or refractory multiple myeloma 5	Primary	Withdrawn

C_max

Value	Dose	Analyte	Population
432 ng/mL	40 mg single, intravenous	MELPHALAN plasma	Homo sapiens
419 ng/mL	40 mg 1 times / 4 weeks steady-state, intravenous	MELPHALAN plasma	Homo sapiens
580 ng/mL	40 mg single, intravenous	MELPHALAN plasma	Homo sapiens
580 ng/mL	40 mg single, intravenous	MELPHALAN plasma	Homo sapiens
516 ng/mL	40 mg single, intravenous	MELPHALAN plasma	Homo sapiens
503 ng/mL	40 mg single, intravenous	MELPHALAN plasma	Homo sapiens
161 ng/mL	40 mg single, intravenous	MELPHALAN FLUFENAMIDE plasma	Homo sapiens
87 ng/mL	40 mg single, intravenous	MELPHALAN FLUFENAMIDE plasma	Homo sapiens
433 ng/mL	40 mg single, intravenous	MELPHALAN plasma	Homo sapiens
429 ng/mL	40 mg single, intravenous	MELPHALAN plasma	Homo sapiens
212 ng/mL	14 mg single, oral	MELPHALAN plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
3143 ng × h/mL	40 mg single, intravenous	MELPHALAN plasma	Homo sapiens
2933 ng × h/mL	40 mg 1 times / 4 weeks steady-state, intravenous	MELPHALAN plasma	Homo sapiens
8233 ng × h/mL	40 mg single, intravenous	MELPHALAN plasma	Homo sapiens
8233 ng × h/mL	40 mg single, intravenous	MELPHALAN plasma	Homo sapiens
62222 ng × h/mL	40 mg single, intravenous	MELPHALAN plasma	Homo sapiens
72466 ng × h/mL	40 mg single, intravenous	MELPHALAN plasma	Homo sapiens
3839 ng × h/mL	40 mg single, intravenous	MELPHALAN FLUFENAMIDE plasma	Homo sapiens
1872 ng × h/mL	40 mg single, intravenous	MELPHALAN FLUFENAMIDE plasma	Homo sapiens
52192 ng × h/mL	40 mg single, intravenous	MELPHALAN plasma	Homo sapiens
53938 ng × h/mL	40 mg single, intravenous	MELPHALAN plasma	Homo sapiens
498 ng × h/mL	14 mg single, oral	MELPHALAN plasma	Homo sapiens
12.84 mg × h/L	200 mg/m² single, intravenous	MELPHALAN plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
2.1 min	single, intravenous	MELPHALAN FLUFENAMIDE plasma	Homo sapiens
70 min	single, intravenous	MELPHALAN plasma	Homo sapiens
80 min	40 mg single, intravenous	MELPHALAN plasma	Homo sapiens
80 min	40 mg single, intravenous	MELPHALAN plasma	Homo sapiens
1 h	14 mg single, oral	MELPHALAN plasma	Homo sapiens
75 min	100 mg/m² 1 times / day multiple, intravenous	MELPHALAN plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
70%	100 mg/m² 1 times / day multiple, intravenous		MELPHALAN plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
40 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose	unhealthy, 18–74	DLT: Thrombocytopenia, Neutropenia...
30 mg/m2 1 times / 3 weeks multiple, intravenous MTD	unhealthy, 18–74	DLT: Thrombocytopenia, Neutropenia...
200 mg/m2 1 times / 70 days multiple, intravenous MTD	unhealthy, 33–65	Disc. AE: Toxic reaction (NOS), Bacterial infection...
100 mg/m2 1 times / day multiple, intravenous Recommended	unhealthy	Disc. AE: Bone marrow depression, Hypersensitivity reaction...
55 mg 1 times / week multiple, intravenous MTD\|Highest studied dose	unhealthy, ADULT

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AEs

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AE	Significance	Dose	Population
Neutropenia	grade 4, 57% DLT	40 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose	unhealthy, 18–74
Thrombocytopenia	grade 4, 57% DLT	40 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose	unhealthy, 18–74
Neutropenia	grade 4, 44% DLT	30 mg/m2 1 times / 3 weeks multiple, intravenous MTD	unhealthy, 18–74
Thrombocytopenia	grade 4, 44% DLT	30 mg/m2 1 times / 3 weeks multiple, intravenous MTD	unhealthy, 18–74
Toxic reaction (NOS)	grade 4, 1.8% Disc. AE	200 mg/m2 1 times / 70 days multiple, intravenous MTD	unhealthy, 33–65

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 1,087 activator 150 inhibitor 2,252	inhibitor 2,438	inhibitor 2,507	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
MRP4 290 MRP2 499 BSEP 550 CYP2A6 879 CYP1A2 2,153 CYP2E1 1,060 CYP19A1 429 MRP3 246 P-gp 1,741 CYP2C19 2,057	MRP1 113 BCRP 697 P-gp 2,052 Aminopepetidase N (CD13) 4

Drug as perpetrator

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Target	Modality	Activity	Metabolite
CYP3A4 2,633	inducer 1,966	inconclusive [Activation 17.7828 uM]	Melphalan 4
CYP19A1 430	inhibitor 4,027	inconclusive [IC50 32.954 uM]	Melphalan 4
CYP3A4 2,633	activator 342	no [Activation 3.1623 uM]	Melphalan 4
BSEP 554	inhibitor 4,027	no [IC50 >133 uM]	Melphalan 4
MRP2 625	inhibitor 4,027	no [IC50 >133 uM]	Melphalan 4

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Drug as victim

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Target	Modality	Activity	Metabolite
BCRP 697	substrate 4,014	no
MRP1 113	substrate 4,014	no
P-gp 2,052	substrate 4,014	yes [IC50 41.8 uM]	Melphalan 4
Aminopepetidase N (CD13) 4	substrate 4,014	yes
P-gp 2,052	substrate 4,014	yes

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:28876	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:28876
ChemicalBook	CB2492687	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB2492687
eMolecules	525665	https://www.emolecules.com/cgi-bin/more?vid=525665
MolPort	MolPort-003-665-535	https://www.molport.com/shop/molecule-link/MolPort-003-665-535
ZINC	ZINC000000001673	http://zinc15.docking.org/substances/ZINC000000001673

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PubMed

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Title	Date	PubMed
Carcinoma of the breast. Occurence after treatment with melphalan for multiple myeloma.	1976 Oct 4	183029
Altered pharmacokinetics in the mechanism of chemosensitization: effects of nitroimidazoles and other chemical modifiers on the pharmacokinetics, antitumour activity and acute toxicity of selected nitrogen mustards.	1986	3698174
L-phenylalanine mustard-dianhydrogalactitol and hyponatremia.	1986	3153241
Prednisone mood disorder with associated catatonia.	1989 Jan-Mar	2742733
Interaction of melphalan and dexamethasone in a human myeloma cell line.	1991 Dec	1806033

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Patents

Sample Use Guides

In Vivo Use Guide

Relapsed or refractory multiple myeloma: recommended dosage of PEPAXTO is 40 mg intravenously over 30 minutes on Day 1 of each 28-day treatment cycle, in combination with dexamethasone.

Route of Administration: Intravenous

In Vitro Use Guide

Melflufen showed activity with cytotoxic IC50-values in the submicromolar range (0.011-0.92 uM) in the cell lines. In the primary cultures melflufen yielded slightly lower IC50-values (2.7 nM to 0.55 uM). Treated cell lines exhibited a clear accumulation in the G2/M-phase of the cell cycle.

Substance Class	Chemical
Record UNII	F70C5K4786
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

MELPHALAN FLUFENAMIDE

Official Name

English

melphalan flufenamide [INN]

Preferred Name

English

L-PHENYLALANINE, 4-(BIS(2-CHLOROETHYL)AMINO)-L-PHENYLALANYL-4-FLUORO-, ETHYL ESTER

Systematic Name

English

PRODRUG J1

Code

English

J-1

Code

English

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Classification Tree

Code System

Code

Mustard Agent

NCI_THESAURUS

C697

Antineoplastic Agent

NCI_THESAURUS

C1742

Positive

EU-Orphan Drug

EU/3/15/1463

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Code System

Code

Type

Description

EPA CompTox

DTXSID40191461

PRIMARY

PUBCHEM

9935639

PRIMARY

RXCUI

2531369

PRIMARY

WIKIPEDIA

Melphalan flufenamide

PRIMARY

SMS_ID

100000177159

PRIMARY

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ACTIVE MOIETY

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Name	Property Type	Amount	Referenced Substance	Parameters
Volume of Distribution	PHARMACOKINETIC	35 LITERS (average)	`F70C5K4786` MELPHALAN FLUFENAMIDE

Biological Half-life	PHARMACOKINETIC	2.1 minutes (average)	`F70C5K4786` MELPHALAN FLUFENAMIDE

Tmax	PHARMACOKINETIC	30 minutes (average)	`F70C5K4786` MELPHALAN FLUFENAMIDE	Melphalan flufenamide peak plasma concentrations were reached during the 30-minute infusion. PHARMACOKINETIC

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator