Raloxifene Evista

Ball-and-Stick Model

Space-filling Model

Ball-and-Stick Model

: Carbon = Hydrogen A = Oxygen M = Nitrogen = Sulfur

Space-filling Model

: Carbon = Hydrogen A = Oxygen M = Nitrogen = Sulfur

Year of discovery: 1982; Year of introduction: 1997 (Eli Lilly); Drug category: Selective estrogen receptor modulator (SERM); Main uses: Prevention and treatment of osteoporosis.

Raloxifene is a synthetic compound which acts as an estrogen on bone, but as an antiestrogen in other tissues. It is a member of a class known as selective estrogen receptor modulators (SERM).1

A reduced level of estrogen in postmenopausal women is a major risk factor for osteoporosis. Unfortunately, the use of natural estrogens for the treatment and prevention of osteoporosis is accompanied by an increased risk of uterine and breast cancer. Although the combination of estrogen with progestin in hormone replacement therapy (HRT) is protective against uterine cancer, it leads to an increased risk of coronary heart disease, invasive breast cancer, stroke and pulmonary embolism.

Estrogens exert a wide range of effects by binding to estrogen receptors (ER) that occur in various tissues. The two known types of estrogen receptors, ERa and ERp are ligand-activated transcription factors that activate gene expression. Different tissues express the two receptor subtypes in different proportions. Binding of estrogen to these receptors initiates conformational changes and dimerization leading to structures that have an increased ability to complex with specific segments of DNA, termed estrogen response elements. The estrogen receptor/DNA complex recruits further coactivators and other proteins leading to the formation of an organized molecular assembly that initiates transcription. The conformation that the estrogen receptor assumes when bound to an antagonist is different from that occupied by an agonist. The antagonist conformation results in a reduced ability to initiate transcription.

The first estrogen receptor modulators were discovered because these compounds were found to produce a tissue-specific response upon binding to estrogen receptors. This discovery stimulated the search for substances that have beneficial estrogenic effects in certain tissues (e.g., bone, brain, liver), but antagonistic or no activity in other tissues (e.g., breast and endometrium), where estrogenic action is undesirable. The tissue-specific activation produced by these substances arises because the geometry of the SERM-ER complexes varies. These variations lead to the recruitment of different co-activators and differences in gene activation.2 Raloxifene, a selective estrogen receptor modulator developed by Eli Lilly, is an agonist at bone estrogen receptors and decreases bone resorption. It was approved for the prevention and treatment of osteoporosis in 2002. Raloxifene also decreases the level of LDL cholesterol without affecting HDL cholesterol. Raloxifene is an estrogen receptor antagonist in breast tissue and is effective in reducing the occurrence of breast cancer in high risk patients, in common with tamoxifen (Nolvadex), another selective estrogen receptor modulator developed for the treatment of breast cancer. The binding of raloxifene to the estrogen receptor is depicted in the figure below.3

Glu353

1. Drugs 2000, 60, 370-411; 2. Reproduction, Fertility and Development 2001, 13, 331-336; 3. Nature 1997, 389, 753758 (1ERR); Refs. p. 106

Glu353

1. Drugs 2000, 60, 370-411; 2. Reproduction, Fertility and Development 2001, 13, 331-336; 3. Nature 1997, 389, 753758 (1ERR); Refs. p. 106

0 = Carbon = Hydrogen ^ = Oxygen ^ = Nitrogen ^ = Sulfur

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