Chemistry:Endoxifen

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Short description: Chemical compound
Endoxifen
Endoxifen.svg
Clinical data
Trade namesZonalta
Other names4-Hydroxy-N-desmethyltamoxifen; Desmethylhydroxytamoxifen
Routes of
administration		By mouth
Identifiers
CAS Number
PubChem CID
UNII
ChEMBL
PDB ligand
Chemical and physical data
FormulaC25H27NO2
Molar mass373.496 g·mol−1
3D model (JSmol)

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]

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]

References

  1. ↑ "Z-endoxifen hydrochloride". NCI Drug Dictionary. https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=693335. 
  2. ↑ 2.0 2.1 "Endoxifen - Intas Pharmaceuticals/Jina pharmaceuticals - AdisInsight". https://adisinsight.springer.com/drugs/800036114. 
  3. ↑ "Endoxifen's molecular mechanisms of action are concentration dependent and different than that of other anti-estrogens". PLOS ONE 8 (1): e54613. 2013. doi:10.1371/journal.pone.0054613. PMID 23382923. Bibcode: 2013PLoSO...854613H. 
  4. ↑ "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. March 2009. doi:10.1158/0008-5472.CAN-08-3933. PMID 19244106. 
  5. ↑ "The effects of a novel hormonal breast cancer therapy, endoxifen, on the mouse skeleton". PLOS ONE 9 (5): e98219. 2014. doi:10.1371/journal.pone.0098219. PMID 24853369. Bibcode: 2014PLoSO...998219G. 
  6. ↑ "Breast cancer: a disease of subtypes". Cancer Forum 40 (3). 2016. http://cancerforum.org.au/forum/2016/november/breast-cancer-a-disease-of-subtypes/. 
  7. ↑ 7.0 7.1 "List of new drugs approved in the year 2019 till date". 1 October 2021. p. 4. https://cdsco.gov.in/opencms/resources/UploadCDSCOWeb/2018/UploadApprovalNewDrugs/newdrugaapproaldec2019.pdf. 
  8. ↑ 8.0 8.1 8.2 "Drug Fact Sheet - Zonalta". Intas Pharmaceuticals. 1 October 2021. https://zonalta.in/wp-content/uploads/2021/03/10-4731-0-6004212-ZONALTA-PIL-1.pdf. 
  9. ↑ (in en) Drug Discovery for Psychiatric Disorders. Drug Discovery. Royal Society of Chemistry. 2012-11-02. doi:10.1039/9781849734943. ISBN 978-1-84973-365-6. https://pubs.rsc.org/en/content/ebook/978-1-84973-365-6. 
  10. ↑ 10.0 10.1 "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. October 2016. doi:10.1111/cts.12407. PMID 27346789. 
  11. ↑ "Protein kinase C inhibitors: rationale for use and potential in the treatment of bipolar disorder". CNS Drugs 23 (7): 569–82. 2009. doi:10.2165/00023210-200923070-00003. PMID 19552485. 
  12. ↑ 12.0 12.1 "Endoxifen: A new, protein kinase C inhibitor to treat acute and mixed mania associated with bipolar I disorder". Bipolar Disorders 23 (6): 595–603. December 2020. doi:10.1111/bdi.13041. PMID 33368969. 
  13. ↑ 13.0 13.1 "Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen". Breast Cancer Research and Treatment 85 (2): 151–9. May 2004. doi:10.1023/B:BREA.0000025406.31193.e8. PMID 15111773. 
  14. ↑ 14.0 14.1 "Novel Selective Estrogen Receptor Ligand Conjugates Incorporating Endoxifen-Combretastatin and Cyclofenil-Combretastatin Hybrid Scaffolds: Synthesis and Biochemical Evaluation". Molecules 22 (9): 1440. August 2017. doi:10.3390/molecules22091440. PMID 28858267. 
  15. ↑ "Pharmacological relevance of endoxifen in a laboratory simulation of breast cancer in postmenopausal patients". Journal of the National Cancer Institute 106 (10). October 2014. doi:10.1093/jnci/dju283. PMID 25258390. 
  16. ↑ "Endoxifen is a new potent inhibitor of PKC: a potential therapeutic agent for bipolar disorder". Bioorganic & Medicinal Chemistry Letters 20 (8): 2665–7. April 2010. doi:10.1016/j.bmcl.2010.02.024. PMID 20227879. 
  17. ↑ "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. December 2010. doi:10.1038/clpt.2010.196. PMID 20981001. 
  18. ↑ (in en) Issues in Pharmacology, Pharmacy, Drug Research, and Drug Innovation: 2011 Edition. ScholarlyEditions. 2012-01-09. ISBN 978-1-4649-6344-5. https://books.google.com/books?id=axDTrm_qO50C&q=Endoxifen&pg=PT217. 
  19. ↑ "The development of endoxifen for breast cancer". Clinical Advances in Hematology & Oncology 16 (2): 102–105. February 2018. PMID 29741509. 

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