Droloxifene

Last updated

Droloxifene
Droloxifene.svg
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-life 19–37 hours [1] [2]
Identifiers
  • 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 InfoCard 100.102.640 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C26H29NO2
Molar mass 387.523 g·mol−1
3D model (JSmol)
  • CC/C(=C(/C1=CC=C(C=C1)OCCN(C)C)\C2=CC(=CC=C2)O)/C3=CC=CC=C3
  • 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 (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]

Contents

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

Related Research Articles

<span class="mw-page-title-main">Selective estrogen receptor modulator</span> Drugs acting on the estrogen receptor

Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonists/antagonists (ERAAs), are a class of drugs that act on estrogen receptors (ERs). Compared to pure ER agonists–antagonists, SERMs are more tissue-specific, allowing them to selectively inhibit or stimulate estrogen-like action in various tissues.

<span class="mw-page-title-main">Tamoxifen</span> Medication

Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.

<span class="mw-page-title-main">Toremifene</span> Chemical compound

Toremifene, sold under the brand name Fareston among others, is a medication which is used in the treatment of advanced breast cancer in postmenopausal women. It is taken by mouth.

<span class="mw-page-title-main">Chlorotrianisene</span> Chemical compound

Chlorotrianisene (CTA), also known as tri-p-anisylchloroethylene (TACE) and sold under the brand name Tace among others, is a nonsteroidal estrogen related to diethylstilbestrol (DES) which was previously used in the treatment of menopausal symptoms and estrogen deficiency in women and prostate cancer in men, among other indications, but has since been discontinued and is now no longer available. It is taken by mouth.

Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or inhibiting or suppressing estrogen production. Antiestrogens are one of three types of sex hormone antagonists, the others being antiandrogens and antiprogestogens. Antiestrogens are commonly used to stop steroid hormones, estrogen, from binding to the estrogen receptors leading to the decrease of estrogen levels. Decreased levels of estrogen can lead to complications in sexual development.

<span class="mw-page-title-main">Afimoxifene</span> Chemical compound

Afimoxifene, also known as 4-hydroxytamoxifen (4-OHT) and by its tentative brand name TamoGel, is a selective estrogen receptor modulator (SERM) of the triphenylethylene group and an active metabolite of tamoxifen. The drug is under development under the tentative brand name TamoGel as a topical gel for the treatment of hyperplasia of the breast. It has completed a phase II clinical trial for cyclical mastalgia, but further studies are required before afimoxifene can be approved for this indication and marketed.

<span class="mw-page-title-main">Nafoxidine</span> Chemical compound

Nafoxidine or nafoxidine hydrochloride 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. It was developed at around the same time as tamoxifen and clomifene, which are also triphenylethylene derivatives. 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. Nafoxidine was assessed in clinical trials in the treatment of breast cancer and was found to be effective. However, it produced side effects including ichthyosis, partial hair loss, and phototoxicity of the skin in almost all patients, and this resulted in the discontinuation of its development.

<span class="mw-page-title-main">Trioxifene</span> Chemical compound

Trioxifene, or as the salt trioxifene mesylate (USAN), is a selective estrogen receptor modulator (SERM) with competitive binding activity against estradiol for the ERα and antagonistic activity against ERα-mediated gene expression, that was under preclinical and clinical development by Eli Lilly and Company for breast cancer and prostate cancer, but was abandoned. Its affinity for the rat estrogen receptor was reported to be 20% relative to estradiol.

<span class="mw-page-title-main">Triphenylethylene</span> Chemical compound

Triphenylethylene (TPE) is a simple aromatic hydrocarbon that possesses weak estrogenic activity. Its estrogenic effects were discovered in 1937. TPE was derived from structural modification of the more potent estrogen diethylstilbestrol, which is a member of the stilbestrol group of nonsteroidal estrogens.

<span class="mw-page-title-main">Ethamoxytriphetol</span> Chemical compound

Ethamoxytriphetol is a synthetic nonsteroidal antiestrogen that was studied clinically in the late 1950s and early 1960s but was never marketed. MER-25 was first reported in 1958, and was the first antiestrogen to be discovered. It has been described as "essentially devoid of estrogenic activity" and as having "very low estrogenic activity in all species tested". However, some estrogenic effects in the uterus have been observed, so it is not a pure antiestrogen but is, instead, technically a selective estrogen receptor modulator (SERM). For all intents and purposes, it is a nearly pure antiestrogen, however.

<span class="mw-page-title-main">Brilanestrant</span> Discontinued oral cancer remedy

Brilanestrant (INN) is a nonsteroidal combined selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) that was discovered by Aragon Pharmaceuticals and was under development by Genentech for the treatment of locally advanced or metastatic estrogen receptor (ER)-positive breast cancer.

<span class="mw-page-title-main">Etacstil</span> Chemical compound

Etacstil is an orally active, nonsteroidal, combined selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) that was developed for the treatment of estrogen receptor-positive breast cancer. It was shown to overcome antiestrogen resistance in breast cancer by altering the shape of the estrogen receptor, thus exhibiting SERD properties. Etacstil is a tamoxifen derivative and one of the first drugs to overcome tamoxifen-resistance. It is the predecessor of GW-7604, of which etacstil is a prodrug. This is analogous to the case of tamoxifen being a prodrug of afimoxifene (4-hydroxytamoxifen).

<span class="mw-page-title-main">Endoxifen</span> Chemical compound

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.

<span class="mw-page-title-main">Triphenylchloroethylene</span> Synthetic form of estrogen

Triphenylchloroethylene, or triphenylchlorethylene, also known as chlorotriphenylethylene or as phenylstilbene chloride, is a synthetic nonsteroidal estrogen of the triphenylethylene group that was marketed in the 1940s for the treatment of menopausal symptoms, vaginal atrophy, lactation suppression, and all other estrogen-indicated conditions.

<span class="mw-page-title-main">ICI-164384</span> Chemical compound

ICI-164384, also known as N-n-butyl-N-methyl-11-(3,17β-dihydroxyestra-1,3,5 -trien-7α-yl)undecanamide, is a steroidal antiestrogen and a synthetic derivative of estradiol which is closely related to fulvestrant and was never marketed. It is a silent antagonist of the estrogen receptor (ER) with no intrinsic estrogenic activity and hence is a pure antiestrogen, unlike selective estrogen receptor modulators (SERMs) like tamoxifen. The drug was under development by AstraZeneca for the treatment of breast cancer but was discontinued in favor of fulvestrant, which is very similar to ICI-164384 but is more potent in comparison.

<span class="mw-page-title-main">Miproxifene</span> Chemical compound

Miproxifene (INN) is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that was never marketed. It is a derivative of afimoxifene (4-hydroxytamoxifen) in which an additional 4-isopropyl group is present in the β-phenyl ring. The drug has been found to be 3- to 10-fold more potent than tamoxifen in inhibiting breast cancer cell growth in in vitro models. Miproxifene is the active metabolite of miproxifene phosphate (TAT-59), a phosphate ester and prodrug of miproxifene that was developed to improve its water solubility. Miproxifene phosphate was under development for the treatment of breast cancer and reached phase III clinical trials for this indication but development was discontinued.

<span class="mw-page-title-main">Miproxifene phosphate</span> Chemical compound

Miproxifene phosphate is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that was under development in Japan for the treatment of breast cancer but was abandoned and never marketed. It reached phase III clinical trials for this indication before development was discontinued. The drug is a phosphate ester and prodrug of miproxifene (DP-TAT-59) with improved water solubility that was better suited for clinical development. Miproxifene has been found to be 3- to 10-fold as potent as tamoxifen in inhibiting breast cancer cell growth in in vitro models. It is a derivative of afimoxifene (4-hydroxytamoxifen) in which an additional 4-isopropyl group is present in the β-phenyl ring.

<span class="mw-page-title-main">Zindoxifene</span> Chemical compound

Zindoxifene is a nonsteroidal selective estrogen receptor modulator (SERM) that was under development in the 1980s and early 1990s for the treatment of breast cancer but was not marketed. It showed estrogenic-like activity in preclinical studies and failed to demonstrate effectiveness as a treatment for breast cancer in clinical trials. Zindoxifene was the lead compound of the distinct 2-phenylindole class of SERMs, and the marketed SERM bazedoxifene was derived from the major active metabolite of zindoxifene, D-15414. Zindoxifene was first described in 1984.

<span class="mw-page-title-main">Panomifene</span> Chemical compound

Panomifene is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group related to tamoxifen that was under development as an antineoplastic agent by Egis Pharmaceuticals and IVAX Drug Research Institute in the 1990s for the treatment of breast cancer, but it was never marketed. It reached phase II clinical trials before development was terminated. The drug was described in 1981.

References

  1. 1 2 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. 1 2 3 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. 1 2 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. 1 2 "Droloxifene". AdisInsight. Springer Nature Switzerland AG.
  7. 1 2 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). doi:10.2174/138161280401221007111005. PMID   10197034. S2CID   40919336.
  11. 1 2 Wittliff JL, Kerr DA II, Andres SA (2005). "Estrogens IV: Estrogen-Like Pharmaceuticals". In Wexler, P. (ed.). Encyclopedia of Toxicology, 2nd Edition. Vol. Dib–L. Elsevier. pp. 254–258. ISBN   978-0-08-054800-5.
  12. ↑ Morrow M, Jordan VC (2003). Managing Breast Cancer Risk. PMPH-USA. pp. 193–. ISBN   978-1-55009-260-8.
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