Non-steroidal estrogen-receptor antagonists

Details Non-steroidal estrogen-receptor antagonists Non-steroidal estrogen-receptor antagonists

2001-01-31

2002-01-22

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C568S329000, C568S373000

Reexamination Certificate

active

06340774

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to non-steroidal estrogen-receptor (ER) antagonists that are useful as therapeutics in the treatment of advanced stage breast cancer. More particularly, this invention relates to the cloning and heterologous expression of genes encoding ER antagonists. This invention also relates to the use of such expression to overproduce the ER antagonist and analogs thereof.
BACKGROUND OF THE INVENTION
Non-steroidal estrogen-receptor (ER) antagonists are useful in the treatment of advanced stage breast cancer. One class of ER antagonists that has been shown to be particularly useful are the R1128 substances (Y. Hori et al., The Journal of Antibiotics, 46(7): 1055-1062.) These substances are anthraquinone natural products with in vitro and in vivo potency approaching that of Tamoxifen. However, many of these types of ER antagonists exhibit variable effects in different target tissue. For example, tamoxifen acts as an ER antagonist in breast tissue, but an ER agonist in bone (Love, R. R. et al., New England Journal of Medicine 26: 852-856 (1992)) and uterine tissue (Kedar, R. P. et al., Lancet 28: 1318-1321 (1992)). Likewise, Raloxifene is an ER antagonist in breast tissue and an ER agonist in bone but not in uterine tissue (Black, L., et al., J. Clin. Invest. 93: 63-69 (1994)).
Estrogen receptors are transcription factors that bind to estrogen response elements in the promoter region of certain estrogen-related genes. Thus, estrogen-like ligands are useful to modulate transcription of these genes (Katzenellenbogen, J. A. and Katzenellenbogen B. S. (1996) Chem. Biol. 3: 529-536.) Recent studies have suggested that the tissue-dependent variability exhibited by these ligands may be due to differential ligand binding and/or activation of the two ER subtypes, ER-&agr; and ER-&bgr;, which each have different tissue expression patterns and ligand binding characteristics (Mosselman, S. et al. (1996) FEBS Letters 392: 49-53.) It has also been reported that the ligand-bound ERs may modulate transcription activation by binding to different types of DNA enhancer elements, such as the AP1 transcription factors (Paech, K. et al. (1997) Science 277: 1508-1510).
Accordingly, there is thus a significant need for new ER antagonists which can inhibit ER function in a predictable way at both ER-dependent and AP 1-dependent DNA binding sites.
SUMMARY OF THE INVENTION
The present invention includes the estrogen receptor antagonist shown in FIG.
3
. Other aspects of the invention are found throughout the specification.


REFERENCES:
patent: 4188495 (1980-02-01), Althuis et al.
patent: 5480913 (1996-01-01), Liao et al.
Black et al., J. Clin. Invest. (1994) 93:63-69.
Hori et al., The Journal of Antibiotics (1993) 46(7):1055-1062.
Love et al., New England Journal of Medicine (1992) 26:852-856.
Katzenellenbogen and Katzenellenbogen, Chem. Biol. (1996) 3:529-536.
Kedar et al., Lancet (1994) 28:1318-1321.
Mosselman et al., FEBS Letters (1996) 392:49-53.
Paech et al., Science (1997) 277:1508-1510.

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