Description
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 (IC
50～800 nM) and ERβ (IC
50～1600 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.
Originator
Tess Diagnostics and
Pharmaceuticals/Hormos
Medical/QuatRx (Finland)
Uses
Treatment of vaginal atrophy, osteoporosis, and vasomotor symptoms.
Definition
ChEBI: An organochlorine compound that is a selective estrogen receptor modulator; used for treatment of dyspareunia.
Clinical Use
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.
Synthesis
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.
