Nafoxidine

Nafoxidine (INN; developmental code names U-11,000A) or nafoxidine hydrochloride (USAN) is a nonsteroidal selective estrogen receptor modulator (SERM) or partial antiestrogen of the triphenylethylene group that was developed for the treatment of advanced breast cancer by Upjohn in the 1970s but was never marketed.[1][2][3] It was developed at around the same time as tamoxifen and clomifene, which are also triphenylethylene derivatives.[2] The drug was originally synthesized by the fertility control program at Upjohn as a postcoital contraceptive, but was subsequently repurposed for the treatment of breast cancer.[4] Nafoxidine was assessed in clinical trials in the treatment of breast cancer and was found to be effective.[5][6] However, it produced side effects including ichthyosis, partial hair loss, and phototoxicity of the skin in almost all patients,[5] and this resulted in the discontinuation of its development.[4][7]

Nafoxidine
Clinical data
Other namesU-11,000A; NSC-70735
Routes of
administration		By mouth
ATC code
  • None
Identifiers
IUPAC name
  • 1-[2-[4-(6-Methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.222.756
Chemical and physical data
FormulaC29H31NO2
Molar mass425.572 g·mol−1
3D model (JSmol)
SMILES
  • COC1=CC2=C(C=C1)C(=C(CC2)C3=CC=CC=C3)C4=CC=C(C=C4)OCCN5CCCC5
InChI
  • InChI=1S/C29H31NO2/c1-31-26-14-16-28-24(21-26)11-15-27(22-7-3-2-4-8-22)29(28)23-9-12-25(13-10-23)32-20-19-30-17-5-6-18-30/h2-4,7-10,12-14,16,21H,5-6,11,15,17-20H2,1H3
  • Key:JEYWNNAZDLFBFF-UHFFFAOYSA-N

Nafoxidine is a long-acting estrogen receptor ligand, with a nuclear retention in the range of 24 to 48 hours or more.[8]

Comparison of early clinical experience with antiestrogens for advanced breast cancer
Antiestrogen Dosage Year(s) Response rate Toxicity
Ethamoxytriphetol 500–4,500 mg/day 1960 25% Acute psychotic episodes
Clomifene 100–300 mg/day 1964–1974 34% Fears of cataracts
Nafoxidine 180–240 mg/day 1976 31% Cataracts, ichthyosis, photophobia
Tamoxifen 20–40 mg/day 1971–1973 31% Transient thrombocytopeniaa
Footnotes: a = "The particular advantage of this drug is the low incidence of troublesome side effects (25)." "Side effects were usually trivial (26)." Sources: [9][10]

References
  1. J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 848–. ISBN 978-1-4757-2085-3.
  2. JORDAN V. CRAIG; B.J.A. Furr (5 February 2010). Hormone Therapy in Breast and Prostate Cancer. Springer Science & Business Media. pp. 95–96. ISBN 978-1-59259-152-7.
  3. Georg F. Weber (22 July 2015). Molecular Therapies of Cancer. Springer. pp. 361–. ISBN 978-3-319-13278-5.
  4. Hormones and Breast Cancer. Elsevier. 25 June 2013. pp. 32–. ISBN 978-0-12-416676-9.
  5. Coelingh Bennink HJ, Verhoeven C, Dutman AE, Thijssen J (2017). "The use of high-dose estrogens for the treatment of breast cancer". Maturitas. 95: 11–23. doi:10.1016/j.maturitas.2016.10.010. PMID 27889048.
  6. Steinbaum, Fred L.; de Jager, Robert L.; Krakoff, Irwin H. (1978). "Clinical trial of nafoxidine in advanced breast cancer". Medical and Pediatric Oncology. 4 (2): 123–126. doi:10.1002/mpo.2950040207. ISSN 0098-1532. PMID 661750.
  7. Aurel Lupulescu (24 October 1990). Hormones and Vitamins in Cancer Treatment. CRC Press. pp. 95–. ISBN 978-0-8493-5973-6.
  8. Wallach, Edward E.; Hammond, Charles B.; Maxson, Wayne S. (1982). "Current status of estrogen therapy for the menopause". Fertility and Sterility. 37 (1): 5–25. doi:10.1016/S0015-0282(16)45970-4. ISSN 0015-0282. PMID 6277697.
  9. Jensen EV, Jordan VC (June 2003). "The estrogen receptor: a model for molecular medicine". Clin. Cancer Res. 9 (6): 1980–9. PMID 12796359.
  10. Howell A, Jordan VC (2013). "Adjuvant Antihormone Therapy". In Craig JV (ed.). Estrogen Action, Selective Estrogen Receptor Modulators And Women's Health: Progress And Promise. World Scientific. pp. 229–254. doi:10.1142/9781848169586_0010. ISBN 978-1-84816-959-3.


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