Nafoxidine

Nafoxidine (INNTooltip International Nonproprietary Name; developmental code names U-11,000A) or nafoxidine hydrochloride (USANTooltip United States Adopted Name) 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 names	U-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	1845-11-0
PubChem CID	4416
IUPHAR/BPS	4263
ChemSpider	4263
UNII	4RIY10WM82
KEGG	C14212
ChEBI	CHEBI:34881
ChEMBL	ChEMBL28211
CompTox Dashboard (EPA)	DTXSID7022386
ECHA InfoCard	100.222.756
Chemical and physical data
Formula	C29H31NO2
Molar mass	425.572 g·mol−1
3D model (JSmol)	Interactive image
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]

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Comparison of early clinical experience with antiestrogens for advanced breast cancer

Antiestrogen	Dosage	Year(s)	Response rate	Adverse effects
Ethamoxytriphetol	500–4,500 mg/day	1960	25%	Acute psychotic episodes
Clomifene	100–300 mg/day	1964–1974	34%	Risks 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]