MELPHALAN FLUFENAMIDE HYDROCHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C24H30Cl2FN3O3.ClH
Molecular Weight	534.879
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure of MELPHALAN FLUFENAMIDE HYDROCHLORIDE

Structure Search

SMILES

Cl.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=ZCMWSKHHXLCVHI-VROPFNGYSA-N

InChI=1S/C24H30Cl2FN3O3.ClH/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);1H/t21-,22-;/m0./s1

HIDE SMILES / InChI

Molecular Formula	ClH
Molecular Weight	36.461
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	C24H30Cl2FN3O3
Molecular Weight	498.418
Charge	0
Count

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

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/23584492 | https://www.ncbi.nlm.nih.gov/pubmed/29029544 | https://www.oncopeptides.se/en/about-ygalo/http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s029lbl.pdf
Curator's Comment: description was created based on several sources, including,http://www.nhs.uk/ipgmedia/National/Macmillan%20Cancer%20Support/assets/MelphalanMCS5pages.pdf http://www.bloodjournal.org/content/bloodjournal/100/1/224.full.pdf

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 278 Target ID: CHEMBL2311221 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s029lbl.pdf	Crosslinking Agent 81

Conditions

Condition	Modality	Targets	Highest Phase	Product
Multiple myeloma 159 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s029lbl.pdf	Palliative		Approved 8429	ALKERAN Approved Use ALKERAN Tablets are indicated for the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. Launch Date 1964
Epithelial carcinoma of the ovary 4 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s029lbl.pdf	Palliative		Approved 8429	ALKERAN Approved Use ALKERAN Tablets are indicated for the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. Launch Date 1964

C_max

Value	Dose	Co-administered	Analyte	Population
212 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s030lbl.pdf	0.25 mg/kg single, oral dose: 0.25 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		MELPHALAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
12.84 mg × h/L EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/26879446	200 mg/m² single, intravenous dose: 200 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered:		MELPHALAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
498 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s030lbl.pdf	0.25 mg/kg single, oral dose: 0.25 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		MELPHALAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
1 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s030lbl.pdf	0.25 mg/kg single, oral dose: 0.25 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		MELPHALAN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
70% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207155s000lbl.pdf			MELPHALAN plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
40 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose Dose: 40 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 40 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/10656432 Page: p.60	unhealthy, 18–74 n = 7 Health Status: unhealthy Condition: Advanced cancer Age Group: 18–74 Sex: M+F Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/10656432 Page: p.60	DLT: Thrombocytopenia, Neutropenia... Dose limiting toxicities: Thrombocytopenia (grade 4, 57%) Neutropenia (grade 4, 57%) Sources: https://pubmed.ncbi.nlm.nih.gov/10656432 Page: p.60
30 mg/m2 1 times / 3 weeks multiple, intravenous MTD Dose: 30 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 30 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/10656432 Page: p.60	unhealthy, 18–74 n = 9 Health Status: unhealthy Condition: Advanced cancer Age Group: 18–74 Sex: M+F Population Size: 9 Sources: https://pubmed.ncbi.nlm.nih.gov/10656432 Page: p.60	DLT: Thrombocytopenia, Neutropenia... Dose limiting toxicities: Thrombocytopenia (grade 4, 44%) Neutropenia (grade 4, 44%) Sources: https://pubmed.ncbi.nlm.nih.gov/10656432 Page: p.60
200 mg/m2 1 times / 70 days multiple, intravenous MTD Dose: 200 mg/m2, 1 times / 70 days Route: intravenous Route: multiple Dose: 200 mg/m2, 1 times / 70 days Sources: https://pubmed.ncbi.nlm.nih.gov/9720737 Page: p.248, 250	unhealthy, 33–65 n = 55 Health Status: unhealthy Condition: Multiple myeloma Age Group: 33–65 Sex: M+F Population Size: 55 Sources: https://pubmed.ncbi.nlm.nih.gov/9720737 Page: p.248, 250	Disc. AE: Toxic reaction (NOS), Bacterial infection... AEs leading to discontinuation/dose reduction: Toxic reaction (NOS) (grade 4, 1.8%) Bacterial infection (grade 5, 3.6%) Systemic herpes zoster infection (grade 5, 1.8%) Sources: https://pubmed.ncbi.nlm.nih.gov/9720737 Page: p.248, 250
100 mg/m2 1 times / day multiple, intravenous Recommended Dose: 100 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207155s000lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Multiple myeloma Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207155s000lbl.pdf Page: p.1	Disc. AE: Bone marrow depression, Hypersensitivity reaction... AEs leading to discontinuation/dose reduction: Bone marrow depression (severe) Hypersensitivity reaction (2%) Anaphylaxis Gastrointestinal toxicity Nausea Vomiting Diarrhea Mucositis oral Fetal damage Infertility Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207155s000lbl.pdf Page: p.1

AEs

Sourcing

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
MolPort	MolPort-003-665-535	https://www.molport.com/shop/molecule-link/MolPort-003-665-535
ZINC	ZINC000000001673	http://zinc15.docking.org/substances/ZINC000000001673
eMolecules	525665	https://www.emolecules.com/cgi-bin/more?vid=525665

PubMed

Title	Date	PubMed
[Diagnosis and treatment of plasma cell leukemia].	1973 Apr 27	4571885
[Refractory anemia with partial myeloblastosis in multiple myeloma treated with melphalan].	1977 Apr 9-16	194338
Lymphocyte transformation studies in drug hypersensitivity.	1979 May 5	445303
L-phenylalanine mustard-dianhydrogalactitol and hyponatremia.	1986	3153241
Prednisone mood disorder with associated catatonia.	1989 Jan-Mar	2742733
Cytogenetic abnormalities in acute leukemia complicating melphalan-treated multiple myeloma.	1990 Aug 1	2372790
[Enhancing factors in the cardiotoxicity of anthracyclines].	1990 Jan	2327660
[Hepatic veno-occlusive disease in a patient undergoing bone marrow autotransplant after busulfan and melphalan conditioning].	1990 Jan 27	2314142
Amifostine can reduce mucosal damage after high-dose melphalan conditioning for peripheral blood progenitor cellautotransplant: a retrospective study.	2000 Aug	10971385
Myeloblastoma (chloroma) in leukemia: case 2. Meningeal granulocytic sarcoma (chloroma) in essential thrombocythemia.	2000 Dec 1	11099330
A phase I and pharmacokinetic study of melphalan using a 24-hour continuous infusion in patients with advanced malignancies.	2000 Jan	10656432
Coexpression of rat glutathione S-transferase A3 and human cytidine deaminase by a bicistronic retroviral vector confers in vitro resistance to nitrogen mustards and cytosine arabinoside in murine fibroblasts.	2000 May	10830723
In children and adolescents, the pharmacodynamics of high-dose busulfan is dependent on the second alkylating agent used in the combined regimen (melphalan or thiotepa).	2003 Nov	14595385
Polymorphic variation in GSTP1 modulates outcome following therapy for multiple myeloma.	2003 Oct 1	12791655
Cardiac toxicity observed in association with high-dose cyclophosphamide-based chemotherapy for metastatic breast cancer.	2004 Aug	15325671
Effective use of high-dose chemotherapy and autologous stem cell rescue for relapsed adult Wilms' tumor and a novel alteration in intron 1 of the WT1 gene.	2004 Dec	15591903
Overexpression of glutathione-S-transferase, MGSTII, confers resistance to busulfan and melphalan.	2005	15779864
Perspectives for combination therapy to overcome drug-resistant multiple myeloma.	2005 Aug	16019253
New treatments for multiple myeloma.	2005 Dec	16506632
The nitrogen mustard melphalan activates mitogen-activated phosphorylated kinases (MAPK), nuclear factor-kappaB and inflammatory response in lung epithelial cells.	2005 Jul-Aug	16025434
Prediction of genotoxicity of chemical compounds by statistical learning methods.	2005 Jun	15962942
[White blood cell lysis syndrome after autologous peripheral blood stem cell transplantation in the treatment of renal AL amyloidosis. Case report].	2006 Jun	17130952
Bortezomib-dexamethasone combination in a patient with refractory multiple myeloma and impaired renal function.	2006 Jun	16860177
Disseminated necrotizing leukoencephalopathy following low-dose oral methotrexate.	2007 Mar	17355553
Multicentric Castleman disease with secondary AA renal amyloidosis, nephrotic syndrome and chronic renal failure, remission after high-dose melphalan and autologous stem cell transplantation.	2007 Sep	17915620
Cutaneous involvement in multiple myeloma and bortezomib.	2009 Nov	19259673
Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial.	2010 Nov	20864405
Efficient monitoring of in vivo pig-a gene mutation and chromosomal damage: summary of 7 published studies and results from 11 new reference compounds.	2012 Dec	22923490
Corticosteroid treatment inhibits airway hyperresponsiveness and lung injury in a murine model of chemical-induced airway inflammation.	2012 Nov 15	22776411
FDA-approved drugs and other compounds tested as inhibitors of human glutathione transferase P1-1.	2013 Sep 5	23769903
Repairing of N-mustard derivative BO-1055 induced DNA damage requires NER, HR, and MGMT-dependent DNA repair mechanisms.	2015 Sep 22	26208482
Melflufen - a peptidase-potentiated alkylating agent in clinical trials.	2017 Sep 12	29029544

Patents

Sample Use Guides

In Vivo Use Guide

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

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 `Sat Dec 16 12:10:27 GMT 2023` Edited by `admin` on `Sat Dec 16 12:10:27 GMT 2023`
Record UNII	3412470A0V
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

MELPHALAN FLUFENAMIDE HYDROCHLORIDE

Official Name

English

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

Systematic Name

English

J-1 HYDROCHLORIDE

Code

English

MELFLUFEN

Common Name

English

MELPHALAN FLUFENAMIDE HYDROCHLORIDE [ORANGE BOOK]

Common Name

English

ETHYL (2S)-2-((2S)-2-AMINO-3-(4-(BIS(2-CHLOROETHYL)AMINO)PHENYL)PROPANAMIDO)-3-(4-FLUOROPHENYL)PROPANOATE, HYDROCHLORIDE (1:1)

Common Name

English

MELPHALAN FLUFENAMIDE HYDROCHLORIDE [USAN]

Common Name

English

PEPAXTO

Brand Name

English

CK-1535

Code

English

J1 HYDROCHLORIDE

Code

English

MELPHALANYL-P-L-FLUOROPHENYLALANINE ETHYL ESTER HYDROCHLORIDE

Common Name

English

MELFLUFEN HYDROCHLORIDE

Common Name

English

Melphalan flufenamide hydrochloride [WHO-DD]

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

465314