Others SERMs

In addition to those described above, some of the newest compounds emerging in SERM development are ER 3-selective ligands and pathway-selective modulators that target the interaction of the ERs with the transcription factor NFkB. While such compounds are in the early stages of clinical evaluation, thus far they demonstrate great potential for use in the treatment of inflammatory disorders such as arthritis, inflammatory bowel disease, and like other SERMs, cancer [4]. 

The antioxidant effect of tamoxifen has also been postulated to underlie some beneficial cardiovascular effect of this and other SERMs. Oxidative damage of LDL plays an important role in the development of atherosclerosis, and it has been postulated that these highly lipophilic molecules stabilize LDL... 

Pure antiestrogens are distinguishable form other SERMs in terms of their mechanism of action, although both classes of agent mediate their effects through the two types of estrogen receptors (ERa and ER/J). 

Lasofoxifene is a SERM that also protects from bone loss, reduces cholesterol levels, and exerts a positive effect on bone strength in rats, specifically in male models (Ma et al. 2002). This compound is in the final stages of clinical development. Two other SERMs also in advanced phase III trials are bazedoxifene and arzoxifene, both with protective effects against ovariectomy-induced bone loss. Arzoxifene has shown both bone remodeling reduction with positive effects on bone quality as well as a reduction in cholesterol levels in oophorectomized rats (Biskobing2003). 

Other SERMs are currently under development. Diaz Curiel et al. (1998) have proved that a raloxifene analog, LY117018 HC1, is effective in reducing bone loss in OVX rats. In addition, the administration of the substance permits a significant reduction in the minimal effective dose of human parathyroid hormone (PTHh) required in the treatment of osteopenic rats (Hodsman et al. 1999a,b). Two more compounds, FC1271a 41 and HMR-3339 (Ammann et al. 2004), show promising results in preclinical studies. 

The relevance attributed to oxidized lipids, and particularly oxidized LDL, in atherogenesis has precipitated interest in the ability of SERMs to this regard. Ex vivo experiments have confirmed that both tamoxifen and raloxifene exert some protection against the oxidation of LDL particles (Arteaga et al. 2003 Zuckerman and Bryan 1996) and that, interestingly, raloxifene is a more powerful antioxidant than tamoxifen or estradiol. It seems that this antioxidant effect is not mediated by the activation of the ER since pure antiestrogens like ICI 182780 and other SERMs like EM 652 have proven to have similar protective effects on LDL (Hermenegildo et al. 2002) (Fig. 9.4). 

These clinical observations demonstrate that the effect of tamoxifen and other SERMs on the endometrium needs to be studied in depth in order to offer objective evidence-based information on these compounds to our patients. This chapter provides a summary of the information available on the mechanism of action and on the clinical data of SERMs on the endometrium. 

With the recognition that SERMs have differential tissue-dependent effects on ER function, there has been recent interest in the effects of raloxifene, tamoxifen, and other SERMs on mood, sleep, cognitive function, and AD severity. What follows is an analysis of the effects of SERMs on several conditions. 

In respect to other SERMs, Bishai et al. (1999) have communicated a case of intrauterine exposure to clomiphene (100 mg/d for approximately 4 weeks) and neonatal persistent hyperplastic primary vitreous. These same authors mention another described case in humans with congenital retinal aplasia. Regarding raloxifene, no relation to ocular problems has been reported. 

Many centers continue to examine this and other SERMs, for example in countering menopausal bone loss (16), in the hope that they can take the place of tamoxifen and provide a means of avoiding the risks of such complications as endometrial cancer, cataract, and stroke (17-19). 

Efforts continue to develop other SERMs that will capitalize on the beneficial effects of estrogen while minimizing or even reducing the carcinogenic effects of estrogen on other tissues. As newer agents are developed, SERMs may have an expanded role in the treatment of various diseases and perhaps provide a safer and more effective method of estrogen replacement.54,59... 

Ishikawa cell stimulation were then tested in ovariectomized rats for the ability to protect against loss of bone mineral density. It was found that GW5638 had antagonist properties on the uterus and agonist activities on bone and the cardiovascular system [59]. In further experiments it was shown that the biological properties of GW5638 derive from triggering a structural conformation of ER different from the conformations imposed by other SERMs [60]. Recently, several novel SERMs (e.g. bazedoxifene, lasofoxifene) have been identified with a combination of cellular screens, primarily uterine- and breast cell-based assays [61-63] (Scheme 1.4). 

From the benzoxathiins reported thus far, 117 exhibits good prospects for further development. The optimized BSC was also tested on other SERM-type ligands, including raloxifene, bazedoxifene and lasofoxifene [151]. Although some increase in ER affinity was observed, no improvement in the rat uterine profile was observed. This result indicates that the optimized side-chain from the benzoxathiins series is not easily transferable to other estrogen ligands. 

Organometallic derivatives of these species have been much studied [19-22]. There are many other SERMs such as toremifene (marketed as Fareston or Acapo-dene), ormeloxifene eNovex-DS, Centron, or Sevista), idoxifene, and so on [23,24]. 

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