Endoxifen

Last updated
Endoxifen
Endoxifen.svg
Clinical data
Trade names Zonalta
Other names4-Hydroxy-N-desmethyltamoxifen; Desmethylhydroxytamoxifen
Routes of
administration 		By mouth
Identifiers
  • 4-[1-[4-[2-(methylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol
CAS Number
PubChem CID
UNII
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.208.548 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C25H27NO2
Molar mass 373.496 g·mol−1
3D model (JSmol)
  • CCC(=C(C1=CC=C(C=C1)O)C2=CC=C(C=C2)OCCNC)C3=CC=CC=C3
  • InChI=1S/C25H27NO2/c1-3-24(19-7-5-4-6-8-19)25(20-9-13-22(27)14-10-20)21-11-15-23(16-12-21)28-18-17-26-2/h4-16,26-27H,3,17-18H2,1-2H3
  • Key:MHJBZVSGOZTKRH-UHFFFAOYSA-N

Endoxifen, also known as 4-hydroxy-N-desmethyltamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group as well as a protein kinase C (PKC) inhibitor. It is under development for the treatment of estrogen receptor-positive breast cancer and for the treatment of mania in bipolar disorder. [1] [2] It is taken by mouth. [2]

Contents

Endoxifen is an active metabolite of tamoxifen and has been found to be effective in patients that have failed previous hormonal therapies (tamoxifen, aromatase inhibitors, and fulvestrant). [3] [4] [5] The prodrug tamoxifen is metabolized by the CYP2D6 enzyme to produce endoxifen and afimoxifene (4-hydroxytamoxifen). [6]

Currently, endoxifen is approved by Drugs Controller General of India for the acute treatment of manic episode with or without mixed features of Bipolar I disorder. [7] It is manufactured and sold by Intas Pharmaceuticals under the brand name Zonalta. [8]

Medical uses

Bipolar disorder

Endoxifen is used to treat manic or mixed episodes associated with bipolar I disorder in India. [9] [7] It has been found that the endoxifen improves manic symptoms as well as mixed episode symptoms of patients with bipolar I disorder and has been considered an effective and well-tolerated treatment for this condition. [10]

Bipolar disorder is associated with overactive protein kinase C (PKC) intracellular signaling. [11] To date, there have been three phases of clinical trials. And, in the phase III trials, endoxifen reduced the total Young Mania Rating Scale (YMRS) score from 33.1 to 17.8. A significant (p < 0.001) improvement in Montgomery–Åsberg Depression Rating Scale (MADRS) score was observed for endoxifen (4.8 to 2.5). The endoxifen is well-tolerated by the subjects as depicted in the changes in Clinical Global Impression-Severity of Illness scores. [12]

Side effects

The most prevalent side effects for endoxifen include headache, vomiting, insomnia. Other side effects were: gastritis, epigastric discomfort, diarrhea, restlessness, somnolence, etc. [8] Some of the adverse events reported with other therapies for the management of manic episodes of bipolar I disorder were not observed during the clinical development program of endoxifen like reduction in platelet count, change in blood thyroid-stimulating hormone levels. There were no deaths, serious or significant adverse events during the conduct of trials. Overall, endoxifen was found to be well-tolerated and safe in patients of bipolar I disorder with acute manic episodes with or without mixed features. [12] [10] An important caveat here is that the trial was of very short duration (only three weeks). The long-term safety of Endoxifen has not been established among patients with Bipolar Disorder.

Pharmacology

Pharmacodynamics

Selective estrogen receptor modulator

Endoxifen is a selective estrogen receptor modulator (SERM) with estrogenic and antiestrogenic actions. In the first study to evaluate the pharmacology of endoxifen, it showed 25% of the affinity of estradiol for the estrogen receptor (ER) while afimoxifene had 35% of the affinity of estradiol for the ER. [13] The antiestrogenic actions of endoxifen and afimoxifene in this study were very similar. [13] In another study, the affinity of endoxifen for the ERα was 12.1% and its affinity for the ERβ was 4.75% relative to estradiol. [14] For comparison, afimoxifene had relative binding affinities for the ERα and ERβ of 19.0% and 21.5% compared to estradiol, respectively. [14] In yet another investigation, both endoxifen and afimoxifene had 181% of the affinity of estradiol for the ER whereas tamoxifen had 2.8% and N-desmethyltamoxifen had 2.4%. [15]

Protein kinase C inhibition

The exact mechanism by which endoxifen exerts its therapeutic effects has not been established in bipolar I disorder. However, the efficacy of endoxifen could be mediated through protein kinase C (PKC). The PKC represents a family of enzymes highly enriched in the brain, where it plays a major role in regulating both pre-and post-synaptic aspects of neurotransmission. Excessive activation of PKC results in symptoms related to bipolar disorder. The PKC signaling pathway is a target for the actions of two structurally dissimilar antimanic agents – lithium and valproate. [8]

Endoxifen exhibits 4-fold higher potency in inhibiting PKC activity compared to tamoxifen in preclinical studies and is not dependent on the isozyme cytochrome P450 2D6 (CYP2D6) for action on the target tissues. [16]

Pharmacokinetics

Orally administered endoxifen is rapidly absorbed and systemically available. The time to peak (Tmax) is between 4.5 and 6 hours after oral administration. It is not metabolized by cytochrome P450 enzymes. The half-life (t½) life of endoxifen is 52.1 to 58.1 hours. [17]

Research

Endoxifen has been investigated as a potential drug in the treatment of breast cancer. [18] [19]

Related Research Articles

<span class="mw-page-title-main">Anastrozole</span> Chemical compound

Anastrozole, sold under the brand name Arimidex among others, is an antiestrogenic medication used in addition to other treatments for breast cancer. Specifically it is used for hormone receptor-positive breast cancer. It has also been used to prevent breast cancer in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">Selective estrogen receptor modulator</span> Drugs acting on the estrogen receptor

Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.

<span class="mw-page-title-main">Tamoxifen</span> Medication

Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.

Fulvestrant, sold under the brand name Faslodex among others, is an antiestrogenic medication used to treat hormone receptor (HR)-positive metastatic breast cancer in postmenopausal women with disease progression as well as HR-positive, HER2-negative advanced breast cancer in combination with abemaciclib or palbociclib in women with disease progression after endocrine therapy. It is given by injection into a muscle.

<span class="mw-page-title-main">Estrogen receptor</span> Proteins activated by the hormone estrogen

Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors, which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs), which are mostly G protein-coupled receptors. This article refers to the former (ER).

<span class="mw-page-title-main">Raloxifene</span> Chemical compound

Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids. For osteoporosis it is less preferred than bisphosphonates. It is also used to reduce the risk of breast cancer in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">HER2</span> Mammalian protein found in humans

Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently referred to as HER2 or CD340.

<span class="mw-page-title-main">Exemestane</span> Breast cancer medication

Exemestane, sold under the brand name Aromasin among others, is a medication used to treat breast cancer. It is a member of the class of antiestrogens known as aromatase inhibitors. Some breast cancers require estrogen to grow. Those cancers have estrogen receptors (ERs), and are called ER-positive. They may also be called estrogen-responsive, hormonally-responsive, or hormone-receptor-positive. Aromatase is an enzyme that synthesizes estrogen. Aromatase inhibitors block the synthesis of estrogen. This lowers the estrogen level, and slows the growth of cancers.

<span class="mw-page-title-main">Toremifene</span> Chemical compound

Toremifene, sold under the brand name Fareston among others, is a medication which is used in the treatment of advanced breast cancer in postmenopausal women. It is taken by mouth.

<span class="mw-page-title-main">GPER</span> Protein-coding gene in the species Homo sapiens

G protein-coupled estrogen receptor 1 (GPER), also known as G protein-coupled receptor 30 (GPR30), is a protein that in humans is encoded by the GPER gene. GPER binds to and is activated by the female sex hormone estradiol and is responsible for some of the rapid effects that estradiol has on cells.

<span class="mw-page-title-main">Afimoxifene</span> Chemical compound

Afimoxifene, also known as 4-hydroxytamoxifen (4-OHT) and by its tentative brand name TamoGel, is a selective estrogen receptor modulator (SERM) of the triphenylethylene group and an active metabolite of tamoxifen. The drug is under development under the tentative brand name TamoGel as a topical gel for the treatment of hyperplasia of the breast. It has completed a phase II clinical trial for cyclical mastalgia, but further studies are required before afimoxifene can be approved for this indication and marketed.

<span class="mw-page-title-main">Trioxifene</span> Chemical compound

Trioxifene, or as the salt trioxifene mesylate (USAN), is a selective estrogen receptor modulator (SERM) with competitive binding activity against estradiol for the ERα and antagonistic activity against ERα-mediated gene expression, that was under preclinical and clinical development by Eli Lilly and Company for breast cancer and prostate cancer, but was abandoned. Its affinity for the rat estrogen receptor was reported to be 20% relative to estradiol.

<span class="mw-page-title-main">Triphenylethylene</span> Chemical compound

Triphenylethylene (TPE) is a simple aromatic hydrocarbon that possesses weak estrogenic activity. Its estrogenic effects were discovered in 1937. TPE was derived from structural modification of the more potent estrogen diethylstilbestrol, which is a member of the stilbestrol group of nonsteroidal estrogens.

<span class="mw-page-title-main">Ethamoxytriphetol</span> Chemical compound

Ethamoxytriphetol is a synthetic nonsteroidal antiestrogen that was studied clinically in the late 1950s and early 1960s but was never marketed. MER-25 was first reported in 1958, and was the first antiestrogen to be discovered. It has been described as "essentially devoid of estrogenic activity" and as having "very low estrogenic activity in all species tested". However, some estrogenic effects in the uterus have been observed, so it is not a pure antiestrogen but is, instead, technically a selective estrogen receptor modulator (SERM). For all intents and purposes, it is a nearly pure antiestrogen, however.

<span class="mw-page-title-main">Etacstil</span> Chemical compound

Etacstil is an orally active, nonsteroidal, combined selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) that was developed for the treatment of estrogen receptor-positive breast cancer. It was shown to overcome antiestrogen resistance in breast cancer by altering the shape of the estrogen receptor, thus exhibiting SERD properties. Etacstil is a tamoxifen derivative and one of the first drugs to overcome tamoxifen-resistance. It is the predecessor of GW-7604, of which etacstil is a prodrug. This is analogous to the case of tamoxifen being a prodrug of afimoxifene (4-hydroxytamoxifen).

<span class="mw-page-title-main">Droloxifene</span> Chemical compound

Droloxifene, also known as 3-hydroxytamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that was developed originally in Germany and later in Japan for the treatment of breast cancer, osteoporosis in men and postmenopausal women, and cardiovascular disorders but was abandoned and never marketed. It reached phase II and phase III clinical trials for these indications before development was discontinued in 2000. The drug was found to be significantly less effective than tamoxifen in the treatment of breast cancer in two phase III clinical trials.

<span class="mw-page-title-main">High-dose estrogen therapy</span> Type of hormone therapy

High-dose estrogen therapy (HDE) is a type of hormone therapy in which high doses of estrogens are given. When given in combination with a high dose of progestogen, it has been referred to as pseudopregnancy. It is called this because the estrogen and progestogen levels achieved are in the range of the very high levels of these hormones that occur during pregnancy. HDE and pseudopregnancy have been used in medicine for a number of hormone-dependent indications, such as breast cancer, prostate cancer, and endometriosis, among others. Both natural or bioidentical estrogens and synthetic estrogens have been used and both oral and parenteral routes may be used.

<span class="mw-page-title-main">ERX-11</span> Chemical compound

ERX-11, also known as ERα coregulator-binding modulator-11, is a novel antiestrogen and experimental hormonal antineoplastic agent which is being researched for the potential treatment of estrogen receptor-positive breast cancer. It is not a competitive antagonist of the estrogen receptor (ER) like conventional antiestrogens such as tamoxifen or fulvestrant; instead of binding to the ligand-binding site of the ER, ERX-11 interacts with a different part of the ERα and blocks protein–protein interactions of the ERα with coregulators that are necessary for the receptor to act and regulate gene expression. It was designed to bind to the coregulator binding region of the ERα and inhibit the ERα/coactivator interaction, although its precise binding site and mode of action have yet to be fully elucidated and understood. Nonetheless, it is clear that ERX-11 binds within the AF-2 domain of the ERα.

<i>N</i>-Desmethyltamoxifen Chemical compound

N-Desmethyltamoxifen is a major metabolite of tamoxifen, a selective estrogen receptor modulator (SERM). N-Desmethyltamoxifen is further metabolized into endoxifen (4-hydroxy-N-desmethyltamoxifen), which is thought to be the major active form of tamoxifen in the body. In one study, N-desmethyltamoxifen had an affinity for the estrogen receptor of 2.4% relative to estradiol. For comparison, tamoxifen, endoxifen, and afimoxifene (4-hydroxytamoxifen) had relative binding affinities of 2.8%, 181%, and 181%, respectively.

Endocrine therapy is a common treatment for estrogen receptor positive breast cancer. However, resistance to this therapy can develop, leading to relapse and progression of disease. This highlights the need for new strategies to combat this resistance.

References

  1. ↑ "Z-endoxifen hydrochloride". NCI Drug Dictionary.
  2. 1 2 "Endoxifen - Intas Pharmaceuticals/Jina pharmaceuticals - AdisInsight".
  3. ↑ Hawse JR, Subramaniam M, Cicek M, Wu X, Gingery A, Grygo SB, et al. (2013). "Endoxifen's molecular mechanisms of action are concentration dependent and different than that of other anti-estrogens". PLOS ONE. 8 (1): e54613. Bibcode:2013PLoSO...854613H. doi: 10.1371/journal.pone.0054613 . PMC   3557294 . PMID   23382923.
  4. ↑ Wu X, Hawse JR, Subramaniam M, Goetz MP, Ingle JN, Spelsberg TC (March 2009). "The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells". Cancer Research . 69 (5): 1722–7. doi: 10.1158/0008-5472.CAN-08-3933 . PMID   19244106.
  5. ↑ Gingery A, Subramaniam M, Pitel KS, Reese JM, Cicek M, Lindenmaier LB, et al. (2014). "The effects of a novel hormonal breast cancer therapy, endoxifen, on the mouse skeleton". PLOS ONE. 9 (5): e98219. Bibcode:2014PLoSO...998219G. doi: 10.1371/journal.pone.0098219 . PMC   4031133 . PMID   24853369.
  6. ↑ Wilcken N (2016). "Breast cancer: a disease of subtypes". Cancer Forum. 40 (3). Archived from the original on 2016-12-03. Retrieved 2016-11-12.
  7. 1 2 "List of new drugs approved in the year 2019 till date" (PDF). Central Drugs Standard Control Organisation . 1 October 2021. p. 4.
  8. 1 2 3 "Drug Fact Sheet - Zonalta" (PDF). Intas Pharmaceuticals. 1 October 2021.
  9. ↑ Rankovic Z, Bingham M, Hargreaves R (2012-11-02). Drug Discovery for Psychiatric Disorders. Drug Discovery. Royal Society of Chemistry. doi:10.1039/9781849734943. ISBN   978-1-84973-365-6.
  10. 1 2 Ahmad A, Sheikh S, Shah T, Reddy MS, Prasad B, Verma KK, et al. (October 2016). "Endoxifen, a New Treatment Option for Mania: A Double-Blind, Active-Controlled Trial Demonstrates the Antimanic Efficacy of Endoxifen". Clinical and Translational Science . 9 (5): 252–259. doi:10.1111/cts.12407. PMC   5350997 . PMID   27346789.
  11. ↑ Zarate CA, Manji HK (2009). "Protein kinase C inhibitors: rationale for use and potential in the treatment of bipolar disorder". CNS Drugs. 23 (7): 569–82. doi:10.2165/00023210-200923070-00003. PMC   2802274 . PMID   19552485.
  12. 1 2 Ahmad A, Sheikh S, Khan MA, Chaturvedi A, Patel P, Patel R, et al. (December 2020). "Endoxifen: A new, protein kinase C inhibitor to treat acute and mixed mania associated with bipolar I disorder". Bipolar Disorders . 23 (6): 595–603. doi:10.1111/bdi.13041. PMID   33368969. S2CID   229688331.
  13. 1 2 Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV, et al. (May 2004). "Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen". Breast Cancer Research and Treatment . 85 (2): 151–9. doi:10.1023/B:BREA.0000025406.31193.e8. hdl: 2027.42/44223 . PMID   15111773. S2CID   37932.
  14. 1 2 Kelly PM, Keely NO, Bright SA, Yassin B, Ana G, Fayne D, et al. (August 2017). "Novel Selective Estrogen Receptor Ligand Conjugates Incorporating Endoxifen-Combretastatin and Cyclofenil-Combretastatin Hybrid Scaffolds: Synthesis and Biochemical Evaluation". Molecules. 22 (9): 1440. doi: 10.3390/molecules22091440 . PMC   6151695 . PMID   28858267.
  15. ↑ Maximov PY, McDaniel RE, Fernandes DJ, Bhatta P, Korostyshevskiy VR, Curpan RF, Jordan VC (October 2014). "Pharmacological relevance of endoxifen in a laboratory simulation of breast cancer in postmenopausal patients". Journal of the National Cancer Institute . 106 (10). doi:10.1093/jnci/dju283. PMC   4271116 . PMID   25258390.
  16. ↑ Ali SM, Ahmad A, Shahabuddin S, Ahmad MU, Sheikh S, Ahmad I (April 2010). "Endoxifen is a new potent inhibitor of PKC: a potential therapeutic agent for bipolar disorder". Bioorganic & Medicinal Chemistry Letters . 20 (8): 2665–7. doi:10.1016/j.bmcl.2010.02.024. PMID   20227879.
  17. ↑ Ahmad A, Shahabuddin S, Sheikh S, Kale P, Krishnappa M, Rane RC, Ahmad I (December 2010). "Endoxifen, a new cornerstone of breast cancer therapy: demonstration of safety, tolerability, and systemic bioavailability in healthy human subjects". Clinical Pharmacology & Therapeutics . 88 (6): 814–7. doi:10.1038/clpt.2010.196. PMID   20981001. S2CID   24590365.
  18. ↑ Issues in Pharmacology, Pharmacy, Drug Research, and Drug Innovation: 2011 Edition. ScholarlyEditions. 2012-01-09. ISBN   978-1-4649-6344-5.
  19. ↑ Goetz MP (February 2018). "The development of endoxifen for breast cancer". Clinical Advances in Hematology & Oncology. 16 (2): 102–105. PMC   7864591 . PMID   29741509.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.