Droloxifene

Droloxifene (INN, USAN) (former developmental code names FK-435, ICI-79280, K-060, K-21060E, RP-60850), also known as 3-hydroxytamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group[1] 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.[3][4][5][6] It reached phase II and phase III clinical trials for these indications before development was discontinued in 2000.[6][7] The drug was found to be significantly less effective than tamoxifen in the treatment of breast cancer in two phase III clinical trials.[7][8]

Droloxifene
Clinical data
Other namesFK-435; ICI-79280; K-060; K-21060E; RP-60850; 3-Hydroxytamoxifen; 3-OH-TAM
Routes of
administration		Oral
Pharmacokinetic data
Elimination half-life19–37 hours[1][2]
Identifiers
IUPAC name
  • 3-[(E)-1-[4-[2-(Dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.102.640
Chemical and physical data
FormulaC26H29NO2
Molar mass387.523 g·mol−1
3D model (JSmol)
SMILES
  • CC/C(=C(/C1=CC=C(C=C1)OCCN(C)C)\C2=CC(=CC=C2)O)/C3=CC=CC=C3
InChI
  • InChI=1S/C26H29NO2/c1-4-25(20-9-6-5-7-10-20)26(22-11-8-12-23(28)19-22)21-13-15-24(16-14-21)29-18-17-27(2)3/h5-16,19,28H,4,17-18H2,1-3H3/b26-25+
  • Key:ZQZFYGIXNQKOAV-OCEACIFDSA-N

Droloxifene is an analogue of tamoxifen, specifically 3-hydroxytamoxifen, but has been said to have 10- to 60-fold increased affinity for the estrogen receptor[9] and reduced partial estrogen agonistic activity.[5][10] The affinity of droloxifene for the estrogen receptor ranges from 0.2 to 15.2% relative to estradiol in different studies.[11] For comparison, the ranges are 0.06 to 16% for tamoxifen and 0.1 to 12% for clomifene.[11] Droloxifene causes a dose-dependent decrease in luteinizing hormone and follicle-stimulating hormone levels, indicating that it has antigonadotropic activity, and dose-dependently increases sex hormone-binding globulin levels, indicating that it has estrogenic activity in the liver.[2] Similarly to tamoxifen, droloxifene has partial estrogenic effects in the uterus.[12] Unlike tamoxifen, droloxifene does not produce DNA adduct or liver tumors in animals.[2]

See also

References
  1. Oettel M, Schillinger E (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. pp. 158, 299. ISBN 978-3-642-60107-1.
  2. Manni A (15 January 1999). Endocrinology of Breast Cancer. Springer Science & Business Media. pp. 298–. ISBN 978-1-59259-699-7.
  3. Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 472–. ISBN 978-1-4757-2085-3.
  4. Morton IK, Hall JM (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 106–. ISBN 978-0-7514-0499-9.
  5. Jordan VC, Furr BJ (5 February 2010). Hormone Therapy in Breast and Prostate Cancer. Springer Science & Business Media. pp. 200–. ISBN 978-1-59259-152-7.
  6. "Droloxifene". AdisInsight. Springer Nature Switzerland AG.
  7. Ottow E, Weinmann H (8 September 2008). Nuclear Receptors as Drug Targets. John Wiley & Sons. pp. 153–. ISBN 978-3-527-62330-3.
  8. Devita VT, Hellman S, Rosenberg SA (1 April 2003). Progress in Oncology 2003. Jones & Bartlett Learning. pp. 217–. ISBN 978-0-7637-2064-3.
  9. Missailidis S (13 October 2008). Anticancer Therapeutics. John Wiley & Sons. pp. 165–. ISBN 978-0-470-69703-0.
  10. Grese TA, Dodge JA (February 1998). "Selective estrogen receptor modulators (SERMs)". Current Pharmaceutical Design. 4 (1): 71–92 (76). PMID 10197034.
  11. Wittliff, J. L., Kerr II, D. A., & Andres, S. A. (2005). "Estrogens IV: Estrogen-Like Pharmaceuticals". In Wexler, P. (ed.). Encyclopedia of Toxicology, 2nd Edition. Vol. Dib–L. pp. 254–258. ISBN 9780080548005.{{cite book}}: CS1 maint: uses authors parameter (link)
  12. Morrow M, Jordan VC (2003). Managing Breast Cancer Risk. PMPH-USA. pp. 193–. ISBN 978-1-55009-260-8.
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