Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-02-27
2004-02-03
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C546S144000, C546S140000, C540S593000, C540S597000, C514S307000, C514S217040, C514S235200, C514S228200, C514S308000, C514S253050, C544S128000, C544S062000, C544S363000
Reexamination Certificate
active
06686351
ABSTRACT:
TECHNICAL FIELD
This invention is generally directed to estrogen antagonists and agonists, including pharmaceutical compositions and uses thereof, and more specifically to compounds which selectively modulate estrogen receptor-beta (ER-&bgr;) activity.
BACKGROUND OF THE INVENTION
The estrogen hormone has a broad spectrum of effects on tissues in both females and males. Many of these biological effects are positive, including maintenance of bone density, cardiovascular protection, central nervous system (CNS) function, and the protection of organ systems from the effects of aging. However, in addition to its positive effects, estrogen also is a potent growth factor in breast and endometrium that increases the risk of cancer.
Until recently, it has been assumed that estrogen binds to a single estrogen receptor (ER) in cells, causing conformational changes that result in release from heat shock proteins and binding of the receptor as a dimer to the so-called estrogen response element in the promoter region of a variety of genes. Further, pharmacologists have generally believed that non-steroidal small molecule ligands compete for binding of estrogen to ER, acting as either antagonists or agonists in each tissue where the estrogen receptor is expressed. Thus, such ligands have traditionally been classified as either pure antagonists or agonists. This is no longer believed to be correct.
Progress over the last few years has shown that ER associates with co-activators (e.g., SRC-1, CBP and SRA) and co-repressors (e.g., SMRT and N-CoR) that modulate the transcriptional activity of ER in a tissue-specific and ligand-specific manner. In addition, evidence now suggests that the majority of estrogen-regulated genes do not have a classical estrogen response element. In such cases, ER interacts with the transcription factors critical for regulation of these genes. Transcription factors known to be modulated in their activity by ER include, for example, AP-1, NF-&kgr;B, C/EBP and Sp-1.
Given the complexity of ER signaling, as well as the various types of tissue that express ER and its co-factors, it is now believed that ER ligands can no longer simply be classified as either pure antagonists or agonists. Therefore, the term “selective estrogen receptor modulator” (SERM) has been coined SERMs bind to ER, but may act as an agonist or antagonist of estrogen in different tissues and on different genes. For example, two of the most well known drugs that behave as SERMs are Tamoxifen (Astra-Zeneca Pharmaceuticals) and Raloxifene (Eli Lilly & Co.). Studies with these two compounds, as well as other SERMs now in development, have demonstrated that the affinity of a SERM for its receptor in many cases does not correlate with its biological activity. Therefore, ligand-binding assays traditionally used in screening for novel ER modulators have not distinguished between tissue-selectivity and agonist/antagonist behavior.
In addition to Tamoxifen and Raloxifene, a number of other compounds have been disclosed to have estrogenic activity, such as those disclosed by Lednicer et al. (
J. Med. Chem.
12, 881, 1969) and Bencze et al. (
J. Med. Chem.
10, 138, 1967), as well as those disclosed in U.S. Pat. Nos. 3,234,090, 3,277,106, and 3,274,213. Further, estrogen agonists/antagonists of the following structure are disclosed in published PCT WO 96/21656 to Cameron et al.:
More recently, a second estrogen receptor, ER-&bgr;, has been identified and cloned (Katzenellenbogen and Korach
Endocrinology
138, 861-2 (1997); Kuiper et al.,
Proc. Natl. Acad. Sci. USA
93, 5925-5930, 1996; Mosselman et al.,
FEBS Lett.
392, 49-53, 1996). ER-&bgr;, and the classical ER renamed ER-&agr;, have significantly different amino acid sequences in the ligand binding domain and carboxy-terminal transactivation domains (~56% amino acid identity), and only 20% homology in their amino-terminal transactivation domain. This suggests that some ligands may have higher affinity to one receptor over the other. Further, ligand-dependent conformational changes of the two receptors, and interaction with co-factors, will result in very different biological actions of a single ligand. In other words, a ligand that acts as an agonist on ER-&agr; may very well serve as an antagonist on ER-&bgr;. An example of such behavior has been described by Paech et al. (
Science
277, 1508-1510, 1997). In that paper, estrogen is reported to activate an AP-1 site in the presence of ER-&agr;, but to inhibit the same site in the presence of ER-&bgr;. In contrast, Raloxifene (Eli Lilly & Co.) and Tamoxifen and ICI-182,780 (Zeneca Pharmaceuticals) stimulate the AP-1 site through ER-&bgr;, but inhibit this site in the presence of ER-&agr;. Another example has been described by Sun et al. (
Endocrinology
140, 800-4, 1999), wherein the R,R-enantiomer of a tetrahydrochrysene is reported to be an agonist on ER-&agr;, but a complete antagonist on ER-&bgr;, while the S,S-enantiomer is an agonist on both receptors.
Furthermore, ER-&agr; and ER-&bgr; have both overlapping and different tissue distributions, as analyzed predominantly by RT-PCR or in-situ hybridization due to a lack of good ER-&bgr; antibodies. Some of these results, however, are controversial, which may be attributable to the method used for measuring ER, the species analyzed (rat, mouse, human) and/or the differentiation state of isolated primary cells. Very often tissues express both ER-&agr; and ER-&bgr;, but the receptors are localized in different cell types. In addition, some tissues (such as kidney) contain exclusively ER-&agr;, while other tissues (such as uterus, pituitary and epidymis) show a great predominance of ER-&agr; (Couse et al.,
Endocrinology
138, 4613-4621, 1997; Kuiper et al.,
Endocrinology
138, 863-870, 1997). In contrast, tissues expressing high levels of ER-&bgr; include prostate, testis, ovaries and certain areas of the brain (Brandenberger et al.,
J. Clin. Endocrinol. Metab.
83, 1025-8, 1998; Enmark et al.,
J. Clinic. Endocrinol. Metabol.
82, 4258-4265, 1997; Laflamme et al.,
J. Neurobiol.
36, 357-78, 1998; Sar and Welsch,
Endocrinology
140, 963-71, 1999; Shughrue et al.,
Endocrinology
138, 5649-52, 1997a; Shughrue et al.,
J. Comp. Neurol.
388, 507-25, 1997b); Chang and Prins,
The Prostate
40, 115-124, 1999.
The development of ER-&agr; (Korach,
Science
266, 1524-1527, 1994) and ER-&bgr; (Krege et al.,
Proc. Natl. Acad. Sci. USA
95, 15677-82, 1998) knockout mice further demonstrate that ER-&bgr; has different functions in different tissues. For example, ER-&agr; knockout mice (male and female) are infertile, females do not display sexual receptivity and males do not have typical male-aggressive behavior (Cooke et al.,
Biol. Reprod.
59, 470-5, 1998; Das et al.,
Proc. Natl. Acad. Sci. USA
94, 12786-12791, 1997; Korach, 1994; Ogawa et al.,
Proc. Natl. Acad. Sci. USA
94, 1476-81, 1997; Rissman et al.,
Endocrinology
138, 507-10, 1997a; Rissman et al.,
Horm. Behav.
31, 232-243, 1997b). Further, the brains of these animals still respond to estrogen in a pattern that is similar to that of wild type animals (Shughrue et al.,
Proc. Natl. Acad. Sci. USA
94, 11008-12, 1997c), and estrogen still inhibits vascular injury caused by mechanical damage (Iafrati et al.,
Nature Med.
3, 545-8, 1997). In contrast, mice lacking the ER-&bgr; develop normally, are fertile and exhibit normal sexual behavior, but have fewer and smaller litters than wild-type mice (Krege et al., 1998), have normal breast development and lactate normally. The reduction in fertility is believed to be the result of reduced ovarian efficiency, and ER-&bgr; is the predominant form of ER in the ovary, being localized in the granulosa cells of maturing follicles. ER-&bgr; knockout mice display signs of prostatic hyperplasia with aging, which suggests that ER-&bgr; may normally protect against abnormal growth (Krege et al., 1998). ER-&agr;/ER-&bgr; double knockout mice are viable, but infertile, and display a postnatal reversal of the ovaries (Couse et al.,
Science
286, 2328-2331, 1999).
I
Bhagwat Shripad S.
Chao Qi
Gayo-Fung Leah M.
Liu Hong
Pennie & Edmonds LLP
Shah Mukund J.
Signal Pharmaceuticals Inc.
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