Identification

Name
Tesmilifene
Accession Number
DB04905
Type
Small Molecule
Groups
Investigational
Description

Tesmilifene is a novel potentiator of chemotherapy which, when added to doxorubicin, achieved an unexpected and very large survival advantage over doxorubicin alone in a randomized trial in advanced breast cancer.

Structure
Thumb
Synonyms
  • Depmpe
  • DPPE
  • N,N-diethyl-2-((4-phenylmethyl)phenoxy)ethanamine
Categories
UNII
I43T3ID6G2
CAS number
98774-23-3
Weight
Average: 283.4079
Monoisotopic: 283.193614427
Chemical Formula
C19H25NO
InChI Key
NFIXBCVWIPOYCD-UHFFFAOYSA-N
InChI
InChI=1S/C19H25NO/c1-3-20(4-2)14-15-21-19-12-10-18(11-13-19)16-17-8-6-5-7-9-17/h5-13H,3-4,14-16H2,1-2H3
IUPAC Name
[2-(4-benzylphenoxy)ethyl]diethylamine
SMILES
CCN(CC)CCOC1=CC=C(CC2=CC=CC=C2)C=C1

Pharmacology

Indication

Intended for the treatment of various forms of cancer.

Pharmacodynamics
Not Available
Mechanism of action

Although the exact mechanism of action is not known, one study (PMID: 16413681) proposes that tesmilifene may be an activating p-gp substrate, which enables the p-gp pump to extrude typical p-gp substrates (such as anthracyclines or taxanes) more efficiently. This process consumes ATP, since the p-gp is absolutely, and highly dependent on ATP hydrolysis. The mechanism of cell death is likely to result not from the presence of chemotherapy inside the cell (in fact the chemotherapy is extruded) but, directly or indirectly, from the enhanced consumption of ATP. The ATP may be consumed below a threshold necessary for survival, or, (more likely) the enhanced ATP production required to maintain ATP levels may result in the generation of reactive oxygen species (ROS) to an extent that overwhelms the cell’s ability to inactivate them. The result would be additional cell death, but only in the mdr+ population. The doxorubicin would continue to act on the drug sensitive remainder of the cell population, but without the help of tesmilifene.

TargetActionsOrganism
AMultidrug resistance protein 1
inducer
Human
UHistamine H1 receptor
antagonist
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Hepatic

Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylamphetamine2,5-Dimethoxy-4-ethylamphetamine may decrease the sedative activities of Tesmilifene.
2,5-Dimethoxy-4-ethylthioamphetamine2,5-Dimethoxy-4-ethylthioamphetamine may decrease the sedative activities of Tesmilifene.
3,4-Methylenedioxyamphetamine3,4-Methylenedioxyamphetamine may decrease the sedative activities of Tesmilifene.
4-Bromo-2,5-dimethoxyamphetamine4-Bromo-2,5-dimethoxyamphetamine may decrease the sedative activities of Tesmilifene.
AbciximabTesmilifene may increase the anticoagulant activities of Abciximab.
AbirateroneThe serum concentration of Tesmilifene can be increased when it is combined with Abiraterone.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Tesmilifene.
AcenocoumarolThe risk or severity of bleeding can be increased when Tesmilifene is combined with Acenocoumarol.
Acetyl sulfisoxazoleThe metabolism of Tesmilifene can be decreased when combined with Acetyl sulfisoxazole.
Acetylsalicylic acidThe risk or severity of adverse effects can be increased when Tesmilifene is combined with Acetylsalicylic acid.
Food Interactions
Not Available

References

General References
  1. Liu J, Tu D, Dancey J, Reyno L, Pritchard KI, Pater J, Seymour LK: Quality of life analyses in a clinical trial of DPPE (tesmilifene) plus doxorubicin versus doxorubicin in patients with advanced or metastatic breast cancer: NCIC CTG Trial MA.19. Breast Cancer Res Treat. 2006 Dec;100(3):263-71. Epub 2006 Jul 6. [PubMed:16823511]
  2. Vincent M: Tesmilifene may enhance breast cancer chemotherapy by killing a clone of aggressive, multi-drug resistant cells through its action on the p-glycoprotein pump. Med Hypotheses. 2006;66(4):715-31. Epub 2006 Jan 18. [PubMed:16413681]
  3. Raghavan D, Brandes LJ, Klapp K, Snyder T, Styles E, Tsao-Wei D, Lieskovsky G, Quinn DI, Ramsey EW: Phase II trial of tesmilifene plus mitoxantrone and prednisone for hormone refractory prostate cancer: high subjective and objective response in patients with symptomatic metastases. J Urol. 2005 Nov;174(5):1808-13; discussion 1813. [PubMed:16217292]
  4. Brandes LJ, Queen GM, LaBella FS: N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine (DPPE) a chemopotentiating and cytoprotective agent in clinical trials: interaction with histamine at cytochrome P450 3A4 and other isozymes that metabolize antineoplastic drugs. Cancer Chemother Pharmacol. 2000;45(4):298-304. [PubMed:10755318]
  5. Brandes LJ, Hogg GR: Study of the in-vivo antioestrogenic action of N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl (DPPE), a novel intracellular histamine antagonist and antioestrogen binding site ligand. J Reprod Fertil. 1990 May;89(1):59-67. [PubMed:2374133]
External Links
PubChem Compound
108092
PubChem Substance
175426896
ChemSpider
97190
BindingDB
50085260
ChEBI
93414
ChEMBL
CHEMBL26424
Wikipedia
Tesmilifene

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentMetastatic/Recurrent Breast Cancer1
2CompletedTreatmentMetastatic Breast Cancer (MBC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00905 mg/mLALOGPS
logP4.65ALOGPS
logP4.64ChemAxon
logS-4.5ALOGPS
pKa (Strongest Basic)9.33ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area12.47 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity89.77 m3·mol-1ChemAxon
Polarizability33.95 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9935
Blood Brain Barrier+0.9482
Caco-2 permeable+0.8072
P-glycoprotein substrateSubstrate0.7041
P-glycoprotein inhibitor IInhibitor0.5341
P-glycoprotein inhibitor IINon-inhibitor0.885
Renal organic cation transporterInhibitor0.7133
CYP450 2C9 substrateNon-substrate0.7941
CYP450 2D6 substrateSubstrate0.6482
CYP450 3A4 substrateSubstrate0.5967
CYP450 1A2 substrateInhibitor0.9707
CYP450 2C9 inhibitorInhibitor0.5636
CYP450 2D6 inhibitorInhibitor0.9575
CYP450 2C19 inhibitorInhibitor0.6944
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8296
Ames testNon AMES toxic0.5749
CarcinogenicityNon-carcinogens0.657
BiodegradationNot ready biodegradable0.9877
Rat acute toxicity2.2808 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.7258
hERG inhibition (predictor II)Inhibitor0.8407
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Diphenylmethanes
Direct Parent
Diphenylmethanes
Alternative Parents
Phenoxy compounds / Phenol ethers / Alkyl aryl ethers / Trialkylamines / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Diphenylmethane / Phenoxy compound / Phenol ether / Alkyl aryl ether / Tertiary aliphatic amine / Tertiary amine / Ether / Organic nitrogen compound / Organic oxygen compound / Organopnictogen compound
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inducer
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Vincent M: Tesmilifene may enhance breast cancer chemotherapy by killing a clone of aggressive, multi-drug resistant cells through its action on the p-glycoprotein pump. Med Hypotheses. 2006;66(4):715-31. Epub 2006 Jan 18. [PubMed:16413681]
  2. Brandes LJ, Queen GM, LaBella FS: N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine (DPPE) a chemopotentiating and cytoprotective agent in clinical trials: interaction with histamine at cytochrome P450 3A4 and other isozymes that metabolize antineoplastic drugs. Cancer Chemother Pharmacol. 2000;45(4):298-304. [PubMed:10755318]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Histamine receptor activity
Specific Function
In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamin...
Gene Name
HRH1
Uniprot ID
P35367
Uniprot Name
Histamine H1 receptor
Molecular Weight
55783.61 Da
References
  1. Brandes LJ, Bogdanovic RP, Cawker MD, LaBella FS: Histamine and growth: interaction of antiestrogen binding site ligands with a novel histamine site that may be associated with calcium channels. Cancer Res. 1987 Aug 1;47(15):4025-31. [PubMed:2886214]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Inducer
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Brandes LJ, Queen GM, LaBella FS: N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine (DPPE) a chemopotentiating and cytoprotective agent in clinical trials: interaction with histamine at cytochrome P450 3A4 and other isozymes that metabolize antineoplastic drugs. Cancer Chemother Pharmacol. 2000;45(4):298-304. [PubMed:10755318]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Brandes LJ, Queen GM, LaBella FS: N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine (DPPE) a chemopotentiating and cytoprotective agent in clinical trials: interaction with histamine at cytochrome P450 3A4 and other isozymes that metabolize antineoplastic drugs. Cancer Chemother Pharmacol. 2000;45(4):298-304. [PubMed:10755318]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d 24-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
References
  1. Brandes LJ, Queen GM, LaBella FS: N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine (DPPE) a chemopotentiating and cytoprotective agent in clinical trials: interaction with histamine at cytochrome P450 3A4 and other isozymes that metabolize antineoplastic drugs. Cancer Chemother Pharmacol. 2000;45(4):298-304. [PubMed:10755318]

Drug created on October 21, 2007 16:23 / Updated on September 13, 2018 15:53