In February 2013, the US FDA approved ospemifene (also referred to as FC1271a), for the treatment ofmoderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy (VVA), due tomenopause. It is estimated that there are 150 million postmenopausal women worldwide with 40–70% suffering from VVA. Ospemifene is a selective estrogen receptor (ER) modulator (SERM) and the first nonhormonal, nonestrogen for the treatment of moderate to severe dyspareunia in women with menopausal VVA. It binds to ERα (IC50～800 nM) and ERβ (IC50～1600 nM) with tissue-specific estrogenic agonist/antagonist effects. Treatment with ospemifene increases the thickness of the vaginal tissue thereby decreasing fragility of the tissue and reducing potential for pain during sexual intercourse.
Tess Diagnostics and
Pharmaceuticals/Hormos
Medical/QuatRx (Finland)
Treatment of vaginal atrophy, osteoporosis, and vasomotor symptoms.
ChEBI: An organochlorine compound that is a selective estrogen receptor modulator; used for treatment of dyspareunia.
Ospemifene is a SERM that is currently in Phase II/III clinical trials for the treatment of postmenopausal
osteoporosis and urogenital atrophy. It is a known metabolite of toremifene, a triphenylethylene
derivative used to treat breast cancer.Ospemifene has been shown to have beneficial effects on the bone
without significant estrogen-related side effects. The beneficial effect observed on bone stems from this
agent's ability to increase osteoblast proliferation and, as a result, to enhance bone mineralization as well as
bone formation. Unlike tamoxifen, ospemifene does not induce osteocyte apoptosis.
The drug can be synthesized succinctly in two steps. First, alkylation
of commercially available 4-hydroxybenzophenone (130)
with ethylene carbonate and catalytic sodium iodide in refluxing
toluene provided benzophenone 131 in 94% yield. This was followed
by a McMurry coupling involving benzophenone 131 with
chloropropiophenone 132 in the presence of zinc powder and titanium
tetrachloride in 2-methyltetrahydrofuran. This reaction gave
rise to a mixture of triphenylethylenes directly as a 5.5:1 ratio of Z
to E isomers which could be separated by crystallization in aqueous
methanol to give a mixture of olefins, 98% of which was comprised
of the desired Z-isomer corresponding to ospemifene (XVII).
The product purity was further improved by recrystallization to
give 99.9% of the Z-isomer in 46% yield from 131. Thus, ospemifene
was synthesized in two steps and 43% overall yield.
