The Discovery and Development of Selective Estrogen Receptor Modulators (SERMs) for Clinical Practice
Philipp Y. Maximov, Theresa M. Lee and V. Craig Jordan
Affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Rd NW, Research Building, Suite E204A, Washington, DC 20057, USA.
Selective estrogen receptor modulators (SERMs) are structurally different compounds that interact with
intracellular estrogen receptors in target organs as estrogen receptor agonists or antagonists. These drugs have been
intensively studied over the past decade and have proven to be a highly versatile group for the treatment of different
conditions associated with postmenopausal women’s health, including hormone responsive cancer and osteoporosis.
Tamoxifen, a failed contraceptive is currently used to treat all stages of breast cancer, chemoprevention in women at high
risk for breast cancer and also has beneficial effects on bone mineral density and serum lipids in postmenopausal women.
Raloxifene, a failed breast cancer drug, is the only SERM approved internationally for the prevention and treatment of
postmenopausal osteoporosis and vertebral fractures. However, although these SERMs have many benefits, they also have
some potentially serious adverse effects, such as thromboembolic disorders and, in the case of tamoxifen, uterine cancer.
These adverse effects represent a major concern given that long-term therapy is required to prevent osteoporosis or
prevent and treat breast cancer.
The search for the ‘ideal’ SERM, which would have estrogenic effects on bone and serum lipids, neutral effects on the
uterus, and antiestrogenic effects on breast tissue, but none of the adverse effects associated with current therapies, is
currently under way. Ospemifene, lasofoxifene, bazedoxifene and arzoxifene, which are new SERM molecules with
potentially greater efficacy and potency than previous SERMs, have been investigated for use in the treatment and
prevention of osteoporosis. These drugs have been shown to be comparably effective to conventional hormone
replacement therapy in animal models, with potential indications for an improved safety profile. Clinical efficacy data
from ongoing phase III trials are available or are awaited for each SERM so that a true understanding of the therapeutic
potential of these compounds can be obtained.
In this article, we describe the discovery and development of the group of medicines called SERMs. The newer SERMs in
late development: ospemifene, lasofoxifene, bazedoxifene, are arzoxifene are described in detail.
Keywords: Arzoxifene, bazedoxifene, lasofoxifene, ospemifene, raloxifene, selective estrogen receptor modulator, tamoxifen
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