SERM mechanism

Selective estrogen receptor modulators (SERMs) are synthetic compounds with partially agonistic and partially antagonistic estrogenic properties. In bone, SERMs inhibit bone resorption via the mechanisms known for estrogens. Major SERMs are tamoxifen, a triphenylethylene compound, and raloxifene. In postmenopausal women, the latter has been shown to prevent bone loss and to reduce fracture risk by 40%. 

Molecnlar Mechanisms of SERM Action as a Means of Understanding their Tissue-Selective Activities... 

We have developed the efficient synthesis of the SERM drug candidate 1 and successfully demonstrated the process on a multiple kilogram scale to support the drug development program. A novel sulfoxide-directed borane reduction of vinyl sulfoxides was discovered. The mechanistic details of this novel reaction were explored and a plausible mechanism proposed. The sequence of asymmetric oxidation of vinyl sulfoxides followed by stereospecific borane reduction to make chiral dihydro-1,4-benzoxathiins was applied to the asymmetric synthesis of a number of other dihydro-1,4-benzoxathiins including the sweetening agent 67. 

Only in-depth knowledge of the mechanisms of the action of estrogens and of other ligands for their receptors will permit a deeper understanding of the foundations on which the specificity of action on tissue for each SERM are based. This is perhaps among those challenging frontiers of knowledge that carry with it the potential to impact society in a profound way. 

Action of Selective Estrogen Receptor Modulators (SERMs) Through the Classical Mechanism of Estrogen Action... 

Figure 3.2 provides a summary of the different mechanisms that have been hypothesized to explain the selective tissue action of SERMs. 

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). 

The evidence that tamoxifen was able to exert estrogenic effects on several tissues like the bone (Love et al. 1992) opened the door to the concept of SERMs, which is explained in detail in Chaps. 2 and 3 of this book. The mechanisms of action of these substances on ERs is explained in detail in Chap. 3. However, it is pertinent to comment on some special aspects of its action on mammary cancer cells. IGF-1 is a key element in growth control of malignant breast cells through endocrine and paracrine pathways. Tamoxifen and its active metabolite are able to inhibit IGF-l-stimulated growth (Jordan... 

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. 

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