Pralatrexate - DrugBank

ID Pharmacology Interactions References Trials Economics Properties Spectra Taxonomy

Targets (2)Enzymes (1)Transporters (1)

Targets (2)Enzymes (1)Transporters (1)Biointeractions (4)

Identification

Name

Pralatrexate

Accession Number

DB06813 (DB05527)

Type

Small Molecule

Groups

Approved

Description

Pralatrexate is an antimetabolite for the treatment of relapsed or refractory peripheral T-cell lymphoma. It is more efficiently retained in cancer cells than methotrexate. FDA approved on September 24, 2009.

Structure

MOL SDF 3D-SDF PDB SMILES InChI View 3D Structure

Synonyms

(2S)-2-((4-((1RS)-1-((2,4-diaminopteridin-6-yl)methyl)but-3-ynyl)benzoyl)amino)pentanedioic acid

(2S)-2-({4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]benzoyl}amino)pentanedioic acid

10-Propargyl-10-deazaaminopterin

N-(4-(1-((2,4-Diamino-6-pteridinyl)methyl)-3-butynyl)benzoyl)-L-glutamic acid

PDX

Pralatrexato

Pralatrexatum

External IDs

Not Available

Product Ingredients

Not Available

Approved Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Folotyn	Injection	20 mg/mL	Intravenous	Allos Therapeutics	2009-09-24	Not applicable	US

Approved Generic Prescription Products

Not Available

Approved Over the Counter Products

Not Available

Unapproved/Other Products

Not Available

International Brands

Not Available

Brand mixtures

Not Available

Categories

UNII

A8Q8I19Q20

CAS number

146464-95-1

Weight

Average: 477.4726
Monoisotopic: 477.176066881

Chemical Formula

C₂₃H₂₃N₇O₅

InChI Key

OGSBUKJUDHAQEA-WMCAAGNKSA-N

InChI

InChI=1S/C23H23N7O5/c1-2-3-14(10-15-11-26-20-18(27-15)19(24)29-23(25)30-20)12-4-6-13(7-5-12)21(33)28-16(22(34)35)8-9-17(31)32/h1,4-7,11,14,16H,3,8-10H2,(H,28,33)(H,31,32)(H,34,35)(H4,24,25,26,29,30)/t14?,16-/m0/s1

IUPAC Name

(2S)-2-({4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]phenyl}formamido)pentanedioic acid

SMILES

NC1=NC2=NC=C(CC(CC#C)C3=CC=C(C=C3)C(=O)N[[email protected]@H](CCC(O)=O)C(O)=O)N=C2C(N)=N1

Pharmacology

Indication

Treatment of relapsed or refractory peripheral T-cell lymphoma.

Structured Indications

Pharmacodynamics

Pralatrexate is a 10-deazaaminopterin analogue of methotrexate. Compared to methotrexate, pralatrexate binds to RTC-1 with 10-times the affinity and is a more potent substrate for FPGS. As a result, pralatrexate is better internalized and retained in cancer cells and is more cytotoxic. Km, pralatrexate = 0.3 μmol/L; Km, methotrexate = 4.8 μmol/L; Vmax/Km (rate of intracellular transport), pralatrexate = 12.6 Vmax/Km (rate of intracellular transport), methotrexate = 0.9

Mechanism of action

The selectivity of pralatrexate for cancer cells is based upon the observation that cancer cells generally have an overexpression of reduced folate carrier protein-1 (RTC-1) compared to normal somatic cells. This carrier protein allows the entrance of pralatrexate into the cell. Upon entering the cell, folypolyglutamate synthase FPGS catalyzes the polyglutamination of pralatrexate so that it is retained inside the cell.
Once inside, pralatrexate competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase. Subsequent depletion of thymidine monophosphate (TMP) occurs so that the cancer cell is unable to synthesize DNA and RNA. As a result, the cancer cell cannot proliferate and is forced to undergo apoptosis. Pralatrexate is more effective against cells that are actively dividing.

Target	Kind	Pharmacological action	Actions	Organism	UniProt ID
Dihydrofolate reductase	Protein	yes	inhibitor	Human	P00374	details
Thymidylate synthase	Protein	yes	inhibitor	Human	P04818	details

Absorption

Pralatrexate demonstrates linear pharmacokinetics with a multiphasic decline with both diasteromers over dose range of 30-325 mg/m^2. Bioavailability, nonformulated preparation = 13 - 20%

Volume of distribution

Vss, R-pralatrexate = 37 L Vss, S-pralatrexate = 105 L

Protein binding

67 - 86% bound to plasma protein, albumin is the major binder. Does not significantly displace substrates from proteins.

Metabolism

No involvement of CYP450 enzyme system or glucuronidases.

Route of elimination

35% of drug is excreted unchanged in the urine (no difference between R- and S- pralatrexate). May be some net renal tubular excretion.

Half life

12-18 hours

Clearance

R- pralatrexate = 191 mL/min S- pralatrexate = 417 mL/min Mean clearance of both enantiomers is 220 mL/min.

Toxicity

Mucositis is the dose-limiting toxicity. Folic acid and vitamin B12 supplements do not prevent mucositis from happening.

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

Drug	Interaction	Drug group
Aceclofenac	The serum concentration of Pralatrexate can be increased when it is combined with Aceclofenac.	Approved
Acetyldigitoxin	Acetyldigitoxin may decrease the cardiotoxic activities of Pralatrexate.	Approved
Acetylsalicylic acid	The serum concentration of Pralatrexate can be increased when it is combined with Acetylsalicylic acid.	Approved, Vet Approved
Adapalene	The serum concentration of Pralatrexate can be increased when it is combined with Adapalene.	Approved
Aminosalicylic Acid	The serum concentration of Pralatrexate can be increased when it is combined with Aminosalicylic Acid.	Approved
Andrographolide	The serum concentration of Pralatrexate can be increased when it is combined with HMPL-004.	Investigational
Anisodamine	The serum concentration of Pralatrexate can be increased when it is combined with Anisodamine.	Investigational
Antipyrine	The serum concentration of Pralatrexate can be increased when it is combined with Antipyrine.	Approved
Apocynin	The serum concentration of Pralatrexate can be increased when it is combined with Acetovanillone.	Investigational
Apremilast	The serum concentration of Pralatrexate can be increased when it is combined with Apremilast.	Approved, Investigational
Azapropazone	The serum concentration of Pralatrexate can be increased when it is combined with Azapropazone.	Withdrawn
Azelastine	The serum concentration of Pralatrexate can be increased when it is combined with Azelastine.	Approved
Balsalazide	The serum concentration of Pralatrexate can be increased when it is combined with Balsalazide.	Approved, Investigational
BCG vaccine	The therapeutic efficacy of Bcg can be decreased when used in combination with Pralatrexate.	Investigational
Benoxaprofen	The serum concentration of Pralatrexate can be increased when it is combined with Benoxaprofen.	Withdrawn
Betulinic Acid	The serum concentration of Pralatrexate can be increased when it is combined with Betulinic Acid.	Investigational
Bevacizumab	Bevacizumab may increase the cardiotoxic activities of Pralatrexate.	Approved, Investigational
Bromfenac	The serum concentration of Pralatrexate can be increased when it is combined with Bromfenac.	Approved
Bucillamine	The serum concentration of Pralatrexate can be increased when it is combined with Bucillamine.	Investigational
Cabazitaxel	The risk or severity of adverse effects can be increased when Cabazitaxel is combined with Pralatrexate.	Approved
Carprofen	The serum concentration of Pralatrexate can be increased when it is combined with Carprofen.	Approved, Vet Approved, Withdrawn
Castanospermine	The serum concentration of Pralatrexate can be increased when it is combined with Castanospermine.	Experimental
Celecoxib	The serum concentration of Pralatrexate can be increased when it is combined with Celecoxib.	Approved, Investigational
Chloroquine	The serum concentration of Pralatrexate can be increased when it is combined with Chloroquine.	Approved, Vet Approved
Choline magnesium trisalicylate	The serum concentration of Pralatrexate can be increased when it is combined with Trisalicylate-choline.	Approved
Clonixin	The serum concentration of Pralatrexate can be increased when it is combined with Clonixin.	Approved
Curcumin	The serum concentration of Pralatrexate can be increased when it is combined with Curcumin.	Investigational
Cyclophosphamide	Cyclophosphamide may increase the cardiotoxic activities of Pralatrexate.	Approved, Investigational
D-Limonene	The serum concentration of Pralatrexate can be increased when it is combined with D-Limonene.	Investigational
Denosumab	The risk or severity of adverse effects can be increased when Denosumab is combined with Pralatrexate.	Approved
dersalazine	The serum concentration of Pralatrexate can be increased when it is combined with dersalazine.	Investigational
Deslanoside	Deslanoside may decrease the cardiotoxic activities of Pralatrexate.	Approved
Diclofenac	The serum concentration of Pralatrexate can be increased when it is combined with Diclofenac.	Approved, Vet Approved
Diflunisal	The serum concentration of Pralatrexate can be increased when it is combined with Diflunisal.	Approved
Digitoxin	Digitoxin may decrease the cardiotoxic activities of Pralatrexate.	Approved
Digoxin	Digoxin may decrease the cardiotoxic activities of Pralatrexate.	Approved
Docetaxel	The risk or severity of adverse effects can be increased when Docetaxel is combined with Pralatrexate.	Approved, Investigational
Droxicam	The serum concentration of Pralatrexate can be increased when it is combined with Droxicam.	Approved
Duvelisib	The serum concentration of Pralatrexate can be increased when it is combined with Duvelisib.	Investigational
E-6201	The serum concentration of Pralatrexate can be increased when it is combined with E6201.	Investigational
Ebselen	The serum concentration of Pralatrexate can be increased when it is combined with Ebselen.	Investigational
Epirizole	The serum concentration of Pralatrexate can be increased when it is combined with Epirizole.	Approved
Etanercept	The serum concentration of Pralatrexate can be increased when it is combined with Etanercept.	Approved, Investigational
Etodolac	The serum concentration of Pralatrexate can be increased when it is combined with Etodolac.	Approved, Investigational, Vet Approved
Etofenamate	The serum concentration of Pralatrexate can be increased when it is combined with Etofenamate.	Approved
Etoricoxib	The serum concentration of Pralatrexate can be increased when it is combined with Etoricoxib.	Approved, Investigational
Evening primrose oil	The serum concentration of Pralatrexate can be increased when it is combined with Evening primrose oil.	Approved
exisulind	The serum concentration of Pralatrexate can be increased when it is combined with exisulind.	Investigational
Fenbufen	The serum concentration of Pralatrexate can be increased when it is combined with Fenbufen.	Approved
Fenoprofen	The serum concentration of Pralatrexate can be increased when it is combined with Fenoprofen.	Approved
Fingolimod	Pralatrexate may increase the immunosuppressive activities of Fingolimod.	Approved, Investigational
Floctafenine	The serum concentration of Pralatrexate can be increased when it is combined with Floctafenine.	Approved, Withdrawn
Flunixin	The serum concentration of Pralatrexate can be increased when it is combined with Flunixin.	Vet Approved
Flurbiprofen	The serum concentration of Pralatrexate can be increased when it is combined with Flurbiprofen.	Approved, Investigational
G17DT	The risk or severity of adverse effects can be increased when Pralatrexate is combined with G17DT.	Investigational
GI-5005	The risk or severity of adverse effects can be increased when Pralatrexate is combined with GI-5005.	Investigational
Higenamine	The serum concentration of Pralatrexate can be increased when it is combined with Higenamine.	Investigational
Ibuprofen	The serum concentration of Pralatrexate can be increased when it is combined with Ibuprofen.	Approved
Ibuproxam	The serum concentration of Pralatrexate can be increased when it is combined with Ibuproxam.	Withdrawn
Icatibant	The serum concentration of Pralatrexate can be increased when it is combined with Icatibant.	Approved
Indomethacin	The serum concentration of Pralatrexate can be increased when it is combined with Indomethacin.	Approved, Investigational
Indoprofen	The serum concentration of Pralatrexate can be increased when it is combined with Indoprofen.	Withdrawn
INGN 201	The risk or severity of adverse effects can be increased when Pralatrexate is combined with INGN 201.	Investigational
INGN 225	The risk or severity of adverse effects can be increased when Pralatrexate is combined with INGN 225.	Investigational
Isoxicam	The serum concentration of Pralatrexate can be increased when it is combined with Isoxicam.	Withdrawn
Kebuzone	The serum concentration of Pralatrexate can be increased when it is combined with Kebuzone.	Experimental
Ketoprofen	The serum concentration of Pralatrexate can be increased when it is combined with Ketoprofen.	Approved, Vet Approved
Ketorolac	The serum concentration of Pralatrexate can be increased when it is combined with Ketorolac.	Approved
Leflunomide	The risk or severity of adverse effects can be increased when Pralatrexate is combined with Leflunomide.	Approved, Investigational
Lisofylline	The serum concentration of Pralatrexate can be increased when it is combined with Lisofylline.	Investigational
Lornoxicam	The serum concentration of Pralatrexate can be increased when it is combined with Lornoxicam.	Approved
Loxoprofen	The serum concentration of Pralatrexate can be increased when it is combined with Loxoprofen.	Approved
Lumiracoxib	The serum concentration of Pralatrexate can be increased when it is combined with Lumiracoxib.	Approved, Investigational
Magnesium salicylate	The serum concentration of Pralatrexate can be increased when it is combined with Magnesium salicylate.	Approved
Masoprocol	The serum concentration of Pralatrexate can be increased when it is combined with Masoprocol.	Approved
Meclofenamic acid	The serum concentration of Pralatrexate can be increased when it is combined with Meclofenamic acid.	Approved, Vet Approved
Mefenamic acid	The serum concentration of Pralatrexate can be increased when it is combined with Mefenamic acid.	Approved
Meloxicam	The serum concentration of Pralatrexate can be increased when it is combined with Meloxicam.	Approved, Vet Approved
Mesalazine	The serum concentration of Pralatrexate can be increased when it is combined with Mesalazine.	Approved
Metamizole	The serum concentration of Pralatrexate can be increased when it is combined with Metamizole.	Withdrawn
Mizoribine	The serum concentration of Pralatrexate can be increased when it is combined with Mizoribine.	Investigational
Mycophenolate mofetil	The serum concentration of Pralatrexate can be increased when it is combined with Mycophenolate mofetil.	Approved, Investigational
Mycophenolic acid	The serum concentration of Pralatrexate can be increased when it is combined with Mycophenolic acid.	Approved
Nabumetone	The serum concentration of Pralatrexate can be increased when it is combined with Nabumetone.	Approved
Nafamostat	The serum concentration of Pralatrexate can be increased when it is combined with Nafamostat.	Approved, Investigational
Naftifine	The serum concentration of Pralatrexate can be increased when it is combined with Naftifine.	Approved
Naproxen	The serum concentration of Pralatrexate can be increased when it is combined with Naproxen.	Approved, Vet Approved
Natalizumab	The risk or severity of adverse effects can be increased when Pralatrexate is combined with Natalizumab.	Approved, Investigational
Nepafenac	The serum concentration of Pralatrexate can be increased when it is combined with Nepafenac.	Approved
Niflumic Acid	The serum concentration of Pralatrexate can be increased when it is combined with Niflumic Acid.	Approved
Nimesulide	The serum concentration of Pralatrexate can be increased when it is combined with Nimesulide.	Approved, Withdrawn
Nitroaspirin	The serum concentration of Pralatrexate can be increased when it is combined with Nitroaspirin.	Investigational
Oleandrin	Anvirzel may decrease the cardiotoxic activities of Pralatrexate.	Experimental
Olopatadine	The serum concentration of Pralatrexate can be increased when it is combined with Olopatadine.	Approved
Olsalazine	The serum concentration of Pralatrexate can be increased when it is combined with Olsalazine.	Approved
Orgotein	The serum concentration of Pralatrexate can be increased when it is combined with Orgotein.	Vet Approved
Ouabain	Ouabain may decrease the cardiotoxic activities of Pralatrexate.	Approved
Oxaprozin	The serum concentration of Pralatrexate can be increased when it is combined with Oxaprozin.	Approved
Oxyphenbutazone	The serum concentration of Pralatrexate can be increased when it is combined with Oxyphenbutazone.	Withdrawn
Paclitaxel	The risk or severity of adverse effects can be increased when Paclitaxel is combined with Pralatrexate.	Approved, Vet Approved
Parecoxib	The serum concentration of Pralatrexate can be increased when it is combined with Parecoxib.	Approved
Phenylbutazone	The serum concentration of Pralatrexate can be increased when it is combined with Phenylbutazone.	Approved, Vet Approved
Pimecrolimus	The risk or severity of adverse effects can be increased when Pimecrolimus is combined with Pralatrexate.	Approved, Investigational
Pirfenidone	The serum concentration of Pralatrexate can be increased when it is combined with Pirfenidone.	Investigational
Piroxicam	The serum concentration of Pralatrexate can be increased when it is combined with Piroxicam.	Approved, Investigational
Probenecid	The serum concentration of Pralatrexate can be increased when it is combined with Probenecid.	Approved
Propacetamol	The serum concentration of Pralatrexate can be increased when it is combined with Propacetamol.	Approved
PTC299	The serum concentration of Pralatrexate can be increased when it is combined with PTC299.	Investigational
Rabies virus inactivated antigen, A	The risk or severity of adverse effects can be increased when Pralatrexate is combined with Rabies vaccine.	Approved
Rabies virus inactivated antigen, A	The therapeutic efficacy of Rabies vaccine can be decreased when used in combination with Pralatrexate.	Approved
Resveratrol	The serum concentration of Pralatrexate can be increased when it is combined with Resveratrol.	Experimental, Investigational
Rindopepimut	The risk or severity of adverse effects can be increased when Pralatrexate is combined with CDX-110.	Investigational
Rofecoxib	The serum concentration of Pralatrexate can be increased when it is combined with Rofecoxib.	Investigational, Withdrawn
Roflumilast	Roflumilast may increase the immunosuppressive activities of Pralatrexate.	Approved
Salicylamide	The serum concentration of Pralatrexate can be increased when it is combined with Salicylamide.	Approved
Salicylic acid	The serum concentration of Pralatrexate can be increased when it is combined with Salicylic acid.	Approved, Vet Approved
Salsalate	The serum concentration of Pralatrexate can be increased when it is combined with Salsalate.	Approved
Sapropterin	The serum concentration of Sapropterin can be decreased when it is combined with Pralatrexate.	Approved, Investigational
Seratrodast	The serum concentration of Pralatrexate can be increased when it is combined with Seratrodast.	Approved
Sipuleucel-T	The therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Pralatrexate.	Approved
SRP 299	The risk or severity of adverse effects can be increased when Pralatrexate is combined with SRP 299.	Investigational
SRT501	The serum concentration of Pralatrexate can be increased when it is combined with SRT501.	Investigational
Sulfamethoxazole	The serum concentration of Pralatrexate can be increased when it is combined with Sulfamethoxazole.	Approved
Sulfasalazine	The serum concentration of Pralatrexate can be increased when it is combined with Sulfasalazine.	Approved
Sulindac	The serum concentration of Pralatrexate can be increased when it is combined with Sulindac.	Approved
Suprofen	The serum concentration of Pralatrexate can be increased when it is combined with Suprofen.	Approved, Withdrawn
Tacrolimus	The risk or severity of adverse effects can be increased when Tacrolimus is combined with Pralatrexate.	Approved, Investigational
Tenoxicam	The serum concentration of Pralatrexate can be increased when it is combined with Tenoxicam.	Approved
Tepoxalin	The serum concentration of Pralatrexate can be increased when it is combined with Tepoxalin.	Vet Approved
Teriflunomide	The serum concentration of Pralatrexate can be increased when it is combined with Teriflunomide.	Approved
TG4010	The risk or severity of adverse effects can be increased when Pralatrexate is combined with TG4010.	Investigational
Tiaprofenic acid	The serum concentration of Pralatrexate can be increased when it is combined with Tiaprofenic acid.	Approved
Tinoridine	The serum concentration of Pralatrexate can be increased when it is combined with Tinoridine.	Investigational
Tofacitinib	Pralatrexate may increase the immunosuppressive activities of Tofacitinib.	Approved, Investigational
Tolfenamic Acid	The serum concentration of Pralatrexate can be increased when it is combined with Tolfenamic Acid.	Approved
Tolmetin	The serum concentration of Pralatrexate can be increased when it is combined with Tolmetin.	Approved
Tranilast	The serum concentration of Pralatrexate can be increased when it is combined with Tranilast.	Approved, Investigational
Trastuzumab	Trastuzumab may increase the cardiotoxic activities of Pralatrexate.	Approved, Investigational
Trimethoprim	The serum concentration of Pralatrexate can be increased when it is combined with Trimethoprim.	Approved, Vet Approved
Valdecoxib	The serum concentration of Pralatrexate can be increased when it is combined with Valdecoxib.	Investigational, Withdrawn
Zaltoprofen	The serum concentration of Pralatrexate can be increased when it is combined with Zaltoprofen.	Approved
Zileuton	The serum concentration of Pralatrexate can be increased when it is combined with Zileuton.	Approved, Investigational, Withdrawn
Zomepirac	The serum concentration of Pralatrexate can be increased when it is combined with Zomepirac.	Withdrawn

Food Interactions

Not Available

References

Synthesis Reference

Not Available

General References

Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799 ]
Gonen N, Assaraf YG: Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012 Aug;15(4):183-210. doi: 10.1016/j.drup.2012.07.002. Epub 2012 Aug 23. [PubMed:22921318 ]
Rodd AL, Ververis K, Karagiannis TC: Safety and efficacy of pralatrexate in the management of relapsed or refractory peripheral T-cell lymphoma. Clin Med Insights Oncol. 2012;6:305-14. doi: 10.4137/CMO.S8536. Epub 2012 Aug 21. [PubMed:23032692 ]

External Links

Resource	Link
KEGG Drug	D05589
PubChem Compound	148121
PubChem Substance	175427094
ChemSpider	130578
ChEBI	71223
ChEMBL	CHEMBL1201746
RxList	http://www.rxlist.com/folotyn-drug.htm
Drugs.com	http://www.drugs.com/cdi/pralatrexate.html
Wikipedia	Pralatrexate

ATC Codes

L01BA05 — Pralatrexate

AHFS Codes

10:00

PDB Entries

Not Available

FDA label

Download (266 KB)

MSDS

Download (479 KB)

Clinical Trials

Phase	Status	Purpose	Conditions	Count
1	Completed	Treatment	Advanced Cancers / Tumors, Solid	1
1	Completed	Treatment	Cutaneous T-Cell Lymphoma (CTCL)	1
1	Completed	Treatment	Cutaneous T-Cell Lymphoma (CTCL) / Mycosis Fungoides (MF) / Primary Cutaneous Anaplastic Large Cell Lymphoma / Sezary Syndrome	1
1	Completed	Treatment	Multiple Myeloma (MM)	1
1	Completed	Treatment	Unspecified Adult Solid Tumor, Protocol Specific	1
1	Recruiting	Treatment	Peripheral T-Cell Lymphoma (PTCL)	1
1	Unknown Status	Treatment	Unspecified Adult Solid Tumor, Protocol Specific	1
1	Withdrawn	Prevention	Non Hodgkin Lymphoma (NHL)	1
1	Withdrawn	Prevention	Non-Small-Cell Lung Carcinoma (NSCLC)	1
1, 2	Active Not Recruiting	Treatment	Cancer, Ovarian / Fallopian Tube Cancer / Peritoneal Cancer	1
1, 2	Active Not Recruiting	Treatment	Peripheral T-Cell Lymphoma (PTCL)	1
1, 2	Completed	Treatment	Lymphoma, B-Cell / Lymphoma, Hodgkins / Peripheral T-Cell Lymphoma (PTCL) / Relapsed or Refractory Lymphoproliferative Malignancies / Waldenstrom's Macroglobulinemia (WM)	1
1, 2	Not Yet Recruiting	Treatment	T-Cell Lymphomas	1
1, 2	Recruiting	Treatment	Lymphoid Malignancies / Lymphoma, Hodgkins / Malignant Lymphomas / Multiple Myeloma (MM) / Non-Hodgkin's Lymphoma (NHL)	1
2	Active Not Recruiting	Treatment	Adult T-cell lymphomas/leukaemias	1
2	Completed	Treatment	Adenocarcinoma of the Esophagus / Adenocarcinomas of the Gastroesophageal Junction / Recurrent Esophageal Cancer / Squamous Cell Carcinoma of the Esophagus / Stage IV Esophageal Cancer	1
2	Completed	Treatment	Adenocarcinomas of the Gastroesophageal Junction / Esophageal Undifferentiated Carcinoma / Gastric Adenocarcinoma / Gastric Squamous Cell Carcinoma / Recurrent Esophageal Adenocarcinoma / Recurrent Esophageal Squamous Cell Carcinoma / Recurrent Gastric Carcinoma / Stage IIIB Esophageal Adenocarcinoma / Stage IIIB Esophageal Squamous Cell Carcinoma / Stage IIIB Gastric Cancer / Stage IIIC Esophageal Adenocarcinoma / Stage IIIC Esophageal Squamous Cell Carcinoma / Stage IIIC Gastric Cancer / Stage IV Esophageal Adenocarcinoma / Stage IV Esophageal Squamous Cell Carcinoma / Stage IV Gastric Cancer / Undifferentiated Gastric Carcinoma	1
2	Completed	Treatment	Bladder Cancers / Neoplasm, Bladder / Transitional Cell Carcinoma	1
2	Completed	Treatment	Cancer of the Breast / Cancer, Breast / Human Mammary Carcinoma / Neoplasms, Breast / Tumors, Breast	1
2	Completed	Treatment	Lung Cancers	1
2	Completed	Treatment	Lymphoma, B-Cell	1
2	Completed	Treatment	Malignant Lymphomas	1
2	Completed	Treatment	Non-Small-Cell Lung Carcinoma (NSCLC)	1
2	Completed	Treatment	Peripheral T-Cell Lymphoma (PTCL)	1
2	Recruiting	Prevention	Peripheral T-cell lymphoma unspecified refractory / Relapsed Peripheral T-Cell Lymphoma	1
2	Unknown Status	Treatment	Anaplastic Large Cell Lymphoma / Angioimmunoblastic T-Cell Lymphoma / Hepatosplenic T-Cell Lymphoma / Peripheral T-Cell Lymphoma (PTCL)	1
3	Active Not Recruiting	Treatment	Peripheral T-cell lymphoma unspecified refractory / Relapsed Peripheral T-Cell Lymphoma	1
3	Terminated	Treatment	Peripheral T-Cell Lymphoma (PTCL)	1
4	Recruiting	Treatment	Peripheral T Cell Lymphoma (PTCL) / Progression, Disease	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage forms

Form	Route	Strength
Injection	Intravenous	20 mg/mL

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US6028071	No	2002-07-16	2022-07-16	US
US7622470	No	2005-05-31	2025-05-31	US
US8299078	No	2005-05-31	2025-05-31	US

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0178 mg/mL	ALOGPS
logP	0.1	ALOGPS
logP	0.33	ChemAxon
logS	-4.4	ALOGPS
pKa (Strongest Acidic)	3.44	ChemAxon
pKa (Strongest Basic)	2.86	ChemAxon
Physiological Charge	-2	ChemAxon
Hydrogen Acceptor Count	11	ChemAxon
Hydrogen Donor Count	5	ChemAxon
Polar Surface Area	207.3 Å²	ChemAxon
Rotatable Bond Count	10	ChemAxon
Refractivity	126.82 m³·mol^-1	ChemAxon
Polarizability	47.31 Å³	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	0	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET features

Property	Value	Probability
Human Intestinal Absorption	-	0.6139
Blood Brain Barrier	+	0.5561
Caco-2 permeable	-	0.7518
P-glycoprotein substrate	Substrate	0.5845
P-glycoprotein inhibitor I	Non-inhibitor	0.9224
P-glycoprotein inhibitor II	Non-inhibitor	0.9921
Renal organic cation transporter	Non-inhibitor	0.938
CYP450 2C9 substrate	Non-substrate	0.8589
CYP450 2D6 substrate	Non-substrate	0.8269
CYP450 3A4 substrate	Non-substrate	0.6396
CYP450 1A2 substrate	Non-inhibitor	0.8654
CYP450 2C9 inhibitor	Non-inhibitor	0.8965
CYP450 2D6 inhibitor	Non-inhibitor	0.9073
CYP450 2C19 inhibitor	Non-inhibitor	0.9178
CYP450 3A4 inhibitor	Non-inhibitor	0.6523
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.934
Ames test	Non AMES toxic	0.8727
Carcinogenicity	Non-carcinogens	0.9543
Biodegradation	Not ready biodegradable	0.9493
Rat acute toxicity	2.6263 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9803
hERG inhibition (predictor II)	Non-inhibitor	0.8735

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum Type	Description	Splash Key
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-004i-1513900000-5596beb52832aa3566cc	View in MoNA
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	Not Available
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	Not Available
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	Not Available
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	Not Available
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	Not Available
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	Not Available

Taxonomy

Description

This compound belongs to the class of chemical entities known as glutamic acid and derivatives. These are compounds containing glutamic acid or a derivative thereof resulting from reaction of glutamic acid at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.

Kingdom

Chemical entities

Super Class

Organic compounds

Class

Organic acids and derivatives

Sub Class

Carboxylic acids and derivatives

Direct Parent

Glutamic acid and derivatives

Alternative Parents

N-acyl-alpha amino acids / Hippuric acids / Pteridines and derivatives / Aromatic monoterpenoids / Bicyclic monoterpenoids / Benzoyl derivatives / Aminopyrimidines and derivatives / Pyrazines / Primary aromatic amines / Imidolactams

Substituents

Glutamic acid or derivatives / Hippuric acid or derivatives / Hippuric acid / N-acyl-alpha-amino acid / N-acyl-alpha amino acid or derivatives / P-cymene / Aromatic monoterpenoid / Monoterpenoid / Bicyclic monoterpenoid / Pteridine

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

terminal acetylenic compound, N-acyl-L-glutamic acid, pteridines (CHEBI:71223 )

Targets

Details

1. Dihydrofolate reductase

Kind: Protein
Organism: Human
Pharmacological action: yes
Actions: inhibitor

General Function:: Nadph binding
Specific Function:: Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.
Gene Name:: DHFR
Uniprot ID:: P00374
Uniprot Name:: Dihydrofolate reductase
Molecular Weight:: 21452.61 Da

References

Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799 ]

Details

2. Thymidylate synthase

Kind: Protein
Organism: Human
Pharmacological action: yes
Actions: inhibitor

General Function:: Thymidylate synthase activity
Specific Function:: Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
Gene Name:: TYMS
Uniprot ID:: P04818
Uniprot Name:: Thymidylate synthase
Molecular Weight:: 35715.65 Da

References

Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799 ]

Enzymes

Details

1. Folylpolyglutamate synthase, mitochondrial

Kind: Protein
Organism: Human
Pharmacological action: unknown
Actions: substrate

General Function:: Tetrahydrofolylpolyglutamate synthase activity
Specific Function:: Catalyzes conversion of folates to polyglutamate derivatives allowing concentration of folate compounds in the cell and the intracellular retention of these cofactors, which are important substrates for most of the folate-dependent enzymes that are involved in one-carbon transfer reactions involved in purine, pyrimidine and amino acid synthesis. Unsubstituted reduced folates are the preferred s...
Gene Name:: FPGS
Uniprot ID:: Q05932
Uniprot Name:: Folylpolyglutamate synthase, mitochondrial
Molecular Weight:: 64608.53 Da

References

Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799 ]

Transporters

Details

1. Folate transporter 1

Kind: Protein
Organism: Human
Pharmacological action: unknown
Actions: substrate

General Function:: Reduced folate carrier activity
Specific Function:: Transporter for the intake of folate. Uptake of folate in human placental choriocarcinoma cells occurs by a novel mechanism called potocytosis which functionally couples three components, namely the folate receptor, the folate transporter, and a V-type H(+)-pump.
Gene Name:: SLC19A1
Uniprot ID:: P41440
Uniprot Name:: Folate transporter 1
Molecular Weight:: 64867.62 Da

References

Gonen N, Assaraf YG: Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012 Aug;15(4):183-210. doi: 10.1016/j.drup.2012.07.002. Epub 2012 Aug 23. [PubMed:22921318 ]

Drug created on September 14, 2010 10:21 / Updated on September 01, 2017 11:31

Structure for DB06813 (Pralatrexate)

Targets

References

References

Enzymes

References

Transporters

References