Compounds and methods for modulation of estrogen receptors

Details Compounds and methods for modulation of estrogen receptors Compounds and methods for modulation of estrogen receptors

2000-07-06

2001-12-18

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S456000, C546S196000, C548S525000, C549S289000

Reexamination Certificate

active

06331562

ABSTRACT:

TECHNICAL FIELD
This invention is generally directed to estrogen antagonists and agonists, and to compounds for inhibiting cytokines, and more specifically to compounds which selectively modulate estrogen receptor-beta (ER-&bgr;) activity, as well as to pharmaceutical compositions and methods related thereto.
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 the breast and endometrium that increases the risk of cancer.
Until recently, it was assumed that estrogen binds to a single estrogen receptor (ER) in cells. As discussed below, this simple view changed significantly when a second ER (ER-&bgr;) was cloned (with the original ER being renamed ER-&agr;), and when co-factors that modulate the ER response were discovered. Ligands can bind to two different ERs which, in the presence of tissue-specific co-activators and/or co-repressors, bind to an estrogen response element in the regulatory region of genes or to other transcription factors. Given the complexity of ER signaling, along with the tissue-specific expression of ER-&agr; and ER-&bgr; and its co-factors, it is now recognized that ER ligands can act as estrogen agonists and antagonists that mimic the positive effects, or block the negative effects, of estrogen in a tissue-specific manner. This has given rise to the discovery of an entirely new class of drugs, referred to as Selective Estrogen Receptor Modulators or SERMs. These drugs have significant potential for the prevention and/or treatment of cancer and osteoporosis, as well as cardiovascular diseases and neurodegenerative diseases such as Alzheimer's
Bone-resorbing diseases, such as osteoporosis, are debilitating conditions which affect a wide population, and to which there is only limited treatment. For example, osteoporosis affects about 50% of women, and about 10% of men, over the age of 50 in the United States. In individuals with osteoporosis. increased loss of bone mass results in fragile bones and, as a result., increased risk of bone fractures. Other bone-resorption diseases, such as Paget's disease and metastatic bone cancer, present similar symptoms.
Bone is a living tissue which contains several different types of cells. In healthy individuals, the amount of bone made by the osteoblastic cells is balanced by the amount of bone removed or resorbed by the osteoclastic cells. In individuals suffering from a bone-resorbing disease, there is an imbalance in the function of these two types of cells. Perhaps the most well known example of such an imbalance is the rapid increase in bone resorption experienced by postmenopausal women. Such accelerated bone lose is attributed to estrogen deficiency associated with menopause. However, the mechanism of how the loss of estrogen results in increased bone resorption has long been debated.
Recently, investigators have suggested that an increase in bone-resorbing cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), may be responsible for postmenopausal bone loss (Kimble et al.,
J. Biol. Chem.
271:28890-28897, 1996), and that inhibitors of these cytokines can partially diminish bone loss following ovariectomy in rodents (Pacifici,
J. Bone Miner Res.
11:1043-1051, 1996). Further, discontinuation of estrogen has been reported to lead to an increase in IL-6 secretion by murine bone marrow and bone cells (Girasole et al.,
J. Clin. Invest.
89:883-891, 1992; Jilka et al., Science 257:88-91, 1992; Kimble et al.,
Endocrinology
136:3054-3061, 1995; Passseri et al.,
Endocrinology
133:822-828, 1993), antibodies against IL-6 can inhibit the increase in osteoclast precursors occurring in estrogen-depleted mice (Girasole et al, supra), and bone loss following ovariectomy does not occur in transgenic mice lacking IL-6 (Poli et al.,
EMBO J.
13:1189-1196, 1994).
Existing treatments for slowing bone loss generally involves administration of compounds such as estrogen, bisphosphonates, calcitonin, and raloxifene. These compounds, however, are generally used for long-term treatments, and have undesirable side effects. Further, such treatments are typically directed to the activity of mature osteoclasts, rather than reducing their formation. For example, estrogen induces the apoptosis of osteoclasts, while calcitonin causes the osteoclasts to shrink and detach from the surface of the bone (Hughes et al., Nat. Med. 2:1132-1136, 1996; (Jilka et al.,
Exp. Hematol.
23:500-506, 1995). Similarly, bisphosphonates decrease osteoclast activity, change their morphology, and increase the apoptosis of osteoclasts (Parfitt et al.,
J. Bone Miner
11:150-159, 1996; Suzuki et al.,
Endocrinology
137:4685-4690, 1996).
Cytokines are also believed to play an important role in a variety of cancers. For example, in the context of prostate cancer, researchers have shown IL-6 to be an autocrine/paracrine growth factor (Seigall et al.,
Cancer Res.
50:7786, 1999). to enhance survival of tumors (Okamoto et al.,
Cancer Res.
57:141-146, 1997), and that neutralizing IL-6 antibodies reduce cell proliferation (Okamoto et al.,
Endocrinology
138:5071-5073, 1997; Borsellino et al.,
Proc. Annu. Meet. Am. Assoc. Cancer Res.
37:A2801, 1996). Similar results have been reported for IL-6 with regard to multiple myeloma (Martinez-Maza et al.,
Res. Immunol.
143:764-769, 1992; Kawano et al.,
Blood
73:517-526, 1989; Zhang et al.,
Blood
74:11-13, 1989; Garrett et al.,
Bone
20:515-520, 1997; and Klein et al.,
Blood
78:1198-12-4, 1991), renal cell carcinoma (Koo et all.
Cancer Immunol.
3597-105, 1002: Tsukamoto et al.,
J. Urol.
148:1778-1782, 1992; and Weissglas et al.,
Endocrinology
138:1879-1885. 1997), and cervical carcinoma (Estuce et al.,
Gynecol. Oncol.
50:15-19, 1993; Tartour et al.,
Cancer Res.
54:6243-6248, 1994; and Iglesias et al.,
Am. J. Pathology
146:944-952, 1995).
Furthermore, IL-6 is also believed to be involved in arthritis, particularly in adjuvant-, collagen- and antigen-induced arthritis (Alonzi et al.,
J. Exp. Med.
187:146-148, 1998; Ohshima et al.,
Proc. Natl. Acad. Sci. USA
95:8222-8226, 1998; and Leisten et al.,
Clin. Immunol. Immunopathol
56:108-115, 1990), and anti-IL-6 antibodies have been reported for treatment of arthritis (Wendling et al.,
J Rheumatol.
20:259-262, 1993). In addition, estrogen has been shown to induce suppression of experimental autoimmune encephalomyelitis and collagen-induced arthritis in mice (Jansson et al.,
Neuroimmunol.
53:203-207, 1994).
As noted above, it had previously 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.
Rather, it is now known that estrogen modulates cellular pharmacology through gene expression, and that the estrogen effect is mediated by estrogen receptors. As noted above, there are currently two estrogen receptors, ER-&agr; and ER-&bgr;. The effect of estrogen receptor on gene regulation can be mediated by a direct binding of ER to the estrogen response element (ERE)-“classical pathway” (Jeltsch et al.,
Nucleic Acids Res.
15:1401-1414, 1987; Bodine et al.,
Endocrinology
139:2048-2057, 1998), binding of ER to other transcription factors such as NF-&kgr;B. C/EBP-&bgr; or AP-1

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