Ospemifene | Selective Estrogen Receptor Modulator | SERM | Treatment for Dyspareunia

Ospemifene [Z-2-(4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy)ethanol] is a third-generation oral, non-estrogen and selective estrogen receptor modulator (SERM), with a unique set of tissue-specific estrogenic agonist/antagonist effects. Ospemifene is the first non-estrogen treatment approved for moderate to severe dyspareunia in women with menopause-related vulvar and vaginal atrophy (VVA) [1]. Ospemifene was first identified as one of the main metabolites of Toremifene.

Ospemifene: 2D and 3D Structure

Dyspareunia is pain during sexual intercourse - encountered by some women, generally those who are post-menopausal. Ospemifene acts similarly to an estrogen on the vaginal epithelium, building vaginal wall thickness which in turn reduces the pain associated with dyspareunia.

Chemically, Ospemifene has triarylethylene framework, a structural variant of the estrogen diethystilbesterol that forms the backbone of a number of non-steroidal estrogen agonists in some tissues as well as antagonists in other tissues (also known as SERMs). It has proven as a novel SERM that acts as agonist by mimicking estrogen in brain, bone and vagina and acts as an antagonist in uterus and breasts. Its biological actions are mediated through binding to estrogen receptors resulting in the activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism).

Hormos Medical is credited with the discovery of Ospemifene. In 2005, Hormos Medical was merged with QuatRx Pharmaceuticals. QuatRx Pharma conducted the global development of the agent and in 2010 licensed it to Shionogi for regulatory filing and commercialization worldwide.

The efficacy and safety of this drug was demonstrated in nine clinical trials with about 2000 participants, and based on the results was Ospemifene approved by the US FDA in February 2013 for the treatment of moderate to severe dyspareunia. Recent reports have also shown its bioactivity in the prevention of osteoporosis and as an anti-breast cancer agent.

Ospemifene (Tradename: Osphena) is once-a-day oral pill with recommended dosage of 60 mg/day, to be taken with meals. The treatment duration should be the shortest possible, taking into account treatment goals and risks to the individual patient, with periodic re-evaluation.

Interaction of Ospemifene with estrogen receptors:

The interaction of Ospemifene with estrogen receptors (ERs) was evaluated by studying the ability of the compound to compete with 17β-[³H]E₂ for binding to purified recombinant human ERα  and ERβ proteins and by comparing that to unlabeled estradiol. Ospemifene displaced estradiol in a concentration-dependent manner, and IC₅₀ values of 827 and 1633 nM were obtained for ER-α and -β, respectively. The IC₅₀ values for 17β-E₂ under the corresponding conditions were 6.8 and. 9.1 nM. The relative binding affinities of Ospemifene calculated from these values were 0.8% and 0.6% for ERα and ERβ, respectively [3].

Ospemifene Synthesis

WO2011089385A1: Shortest route available

Identification:

1H NMR (Estimated) for Ospemifene

Sideeffects:

Ospemifene treatment for up to 52 weeks was generally well tolerated in clinical trials in postmenopausal women. The most common adverse events (AEs, less than 5%) reported are hot flush, urinary tract infection, headache and vaginal spotting. No endometrial hyperplasia or carcinoma, polyps or cancer were observed in any patient in the trials. 

References:

1. McCall, J. L.; et. al. Pharmacologic evaluation of ospemifene. Expert Opin Drug Metab Toxicol 2010, 6(6), 773-779.

2. Eklund, L.; et. al. New processes for producing benzophenone derivatives. WO2011089385A1
3. Qu, Q.; et. al. Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats. Endocrinology 2000, 141(2), 809-820.