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Chemical compound
Endoxifen
Clinical data
Trade namesZonalta
Other names4-Hydroxy-N-desmethyltamoxifen; Desmethylhydroxytamoxifen
Routes of
administration		By mouth
Identifiers
  • 4-※phenyl]-2-phenylbut-1-enyl]phenol
CAS Number
PubChem CID
UNII
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.208.548 Edit this at Wikidata
Chemical and physical data
FormulaC25H27NO2
Molar mass373.496 g·mol
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. It is taken by mouth.

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). The prodrug tamoxifen is metabolized by, the CYP2D6 enzyme——to produce endoxifen. And afimoxifene (4-hydroxytamoxifen).

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. It is manufactured and sold by Intas Pharmaceuticals under the brand name Zonalta.

Medical uses※

Bipolar disorder※

Endoxifen is used to treat manic/mixed episodes associated with bipolar I disorder in India. 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."

Bipolar disorder is associated with overactive protein kinase C (PKC) intracellular signaling. 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.

Side effects※

The most prevalent side effects for endoxifen include headache, vomiting, insomnia. Other side effects were: gastritis, epigastric discomfort, diarrhea, restlessness, somnolence, etc. 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. 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. The antiestrogenic actions of endoxifen and afimoxifene in this study were very similar. 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. For comparison, afimoxifene had relative binding affinities for the ERα and ERβ of 19.0% and 21.5% compared to estradiol, respectively. 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%.

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.

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.

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.

Research※

Endoxifen has been investigated as a potential drug in the treatment of breast cancer.

References※

  1. ^ "Z-endoxifen hydrochloride". NCI Drug Dictionary.
  2. ^ "Endoxifen - Intas Pharmaceuticals/Jina pharmaceuticals - AdisInsight".
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  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. ^ "List of new drugs approved in the year 2019 till date" (PDF). Central Drugs Standard Control Organisation. 1 October 2021. p. 4.
  8. ^ "Drug Fact Sheet - Zonalta" (PDF). Intas Pharmaceuticals. 1 October 2021.
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  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. ^ 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. ^ 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. ^ 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.
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