Editing Selective estrogen receptor modulator (section)

==== Second-generation benzothiophenes ====
[[Image:Raloxifene Chemical Structure V 3.png|thumb|272x272px|class=skin-invert-image|Raloxifene has a benzothiophene group (red) and is connected with a flexible carbonyl hinge to a phenyl 4-piperidinoethoxy side chain (green).]]

Raloxifene belongs to the second-generation [[benzothiophene]] SERM drugs. It has a high affinity for the ER with potent antiestrogenic activity and tissue-specific effects distinct from estradiol.<ref name="Musa_2007" /> Raloxifene is an ER agonist in bone and the cardiovascular system, but in breast tissue and the endometrium it acts as an ER antagonist. It is extensively metabolized by [[glucuronide conjugation]] in the gut and because of that has a low [[bioavailability]] of only 2% while that of tamoxifen and toremifene is approximately 100%.<ref name="Morello_2012" />

The advantage of raloxifene over the triphenylethylene tamoxifen is reduced effect on the uterus. The flexible hinge group, as well as the antiestrogenic phenyl 4-piperidinoethoxy side chain, are important for minimizing uterine effects. Because of its flexibility the side chain can obtain an orthogonal disposition relative to the core<ref name="Miller_2002" /> so that the amine of raloxifene side chain is 1 Å closer than tamoxifens to amino acid Asp-351 in ERα's ligand-binding domain.<ref name="Jensen_2003" /><ref name="Jordan_2003">{{cite journal | vauthors = Jordan VC | title = Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 2. Clinical considerations and new agents | journal = Journal of Medicinal Chemistry | volume = 46 | issue = 7 | pages = 1081–111 | date = Mar 2003 | pmid = 12646017 | doi = 10.1021/jm020450x }}</ref>

The critical role of the intimate relationship between the hydrophobic side chain of raloxifene and the hydrophobic residue of the receptor to change both the shape and charge of the external surface of a SERM-ER complex has been confirmed with raloxifene derivatives. When the interactive distance between raloxifene and Asp-351 is increased from 2.7 Å to 3.5-5 Å it causes increased estrogen-like action of the raloxifene-ERα complex. When the piperidine ring of raloxifene is replaced by [[cyclohexane]], the ligand loses antiestrogenic properties and becomes a full agonist. The interaction between SERM's antiestrogenic side chain and amino acid Asp-351 is the important first step in silencing AF-2. It relocates helix 12 away from the ligand-binding pocket thereby preventing coactivators from binding to the SERM-ER complex.<ref name="Jensen_2003" /><ref name="Jordan_2003" />