Editing Selective estrogen receptor modulator (section)

==== Third-generation ====
[[File:Nafoxidine3.png|thumb|150px|left|class=skin-invert-image|Chemical structure of nafoxidine with the dihydronapthalene group in red.]]
Third-generation compounds display either no uterine stimulation, improved potency, no significant increases in hot flushes or a combination of these attributes.<ref name="Miller_2002" />

The first dihydronapthalene SERM, [[nafoxidine]], was a clinical candidate for the treatment of breast cancer but had side effects including severe phototoxicity. Nafoxidine has all three phenyls constrained in a coplanar arrangement like tamoxifen. But with hydrogenation, the double bond of nafoxidene were reduced, and both phenyls are cis-oriented. The amine-bearing side chain can then adopt an axial conformation and locate this group orthogonally to the plane of the core, like ralofoxifene and other less uterotropic SERMs.{{cn|date=January 2025}}

[[File:Lasofoxifene.png|thumb|150px|class=skin-invert-image|Chemical structure of lasofoxifene shows cis-oriented phenyls.]]

Modifications of nafoxidine resulted in lasofoxifene. Lasofoxifene is among the most potent SERMs reported in protection against bone loss and cholesterol reduction. The excellent oral potency of lasofoxifene has been attributed to reduced intestinal glucuronidation of the phenol.<ref name="Miller_2002" /> Unlike raloxifene, lasofoxifene satisfies the requirement of a [[pharmacophore]] model that predicts resistance to gut wall glucuronidation. The structural requirement is a non-planar topology with the steric bulk close to the plane of a fused bicyclic aromatic system.<ref name="Vajdos_2007">{{cite journal | vauthors = Vajdos FF, Hoth LR, Geoghegan KF, Simons SP, LeMotte PK, Danley DE, Ammirati MJ, Pandit J | title = The 2.0 A crystal structure of the ERalpha ligand-binding domain complexed with lasofoxifene | journal = Protein Science | volume = 16 | issue = 5 | pages = 897–905 | date = May 2007 | pmid = 17456742 | doi = 10.1110/ps.062729207 | pmc=2206632}}</ref> The interactions between the ER and lasofoxifene are consistent with the general features of SERM-ER recognition. Lasofoxifene's large flexible side chain terminates in a pyrrolidine head group and threads its way out toward the surface of the protein, where it interferes directly with the positioning of the AF-2 helix. A salt bridge forms between lasofoxifene and Asp-351. The charge neutralization in this region ER may explain some antiestrogenic effects exerted by lasofoxifene.<ref name=Rosano_2011 />

[[File:Bazedoxifene 2.png|thumb|200px|left|class=skin-invert-image|Bazedoxifene includes an indole system (red) which is connected to an amine through a benzyloxyethyl chain (green).]]

The [[Indole|indole system]] has served as a core unit in SERMs, and when an amine is attached to the indole with a benzyloxyethyl, the resultant compounds were shown to have no preclinical uterine activity while sparing rat bone with full efficacy at low doses. Bazedoxifene is one of those compounds. The core binding domain consists of a 2-phenyl-3-methyl indole and a hexamethylenamine ring at the side chain affecter region. It is metabolized by glucuronidation, with the absolute bioavailability of 6.2%, 3-fold higher than that of raloxifene. It has agonistic effects on bone and lipid metabolism but not on breast and uterine endometrium.<ref name="Kung2009">{{cite journal | vauthors = Kung AW, Chu EY, Xu L | title = Bazedoxifene: a new selective estrogen receptor modulator for the treatment of postmenopausal osteoporosis | journal = Expert Opinion on Pharmacotherapy | volume = 10 | issue = 8 | pages = 1377–85 | date = Jun 2009 | pmid = 19445558 | doi = 10.1517/14656560902980228 | s2cid = 20781017 }}</ref> It is well tolerated and displays no increase in hot flush {{not a typo|incidences}}, uterine hypertrophy or breast tenderness.<ref name="Miller_2002" />

[[File:Ospemifene 2.png|thumb|200px|class=skin-invert-image|Chemical structure of ospemifene. Ethoxy side chain ends with a hydroxy group (red) instead of a dimethylamino group as with first-generation SERMs.]]

Ospemifene is a triphenylethylene and a known metabolite of toremifene. It's structurally very similar to tamoxifen and toremifene. Ospemifene does not have 2-(dimethylamino)ethoxy group as tamoxifen. Structure–activity relationship studies showed that by removing that group of tamoxifen agonistic activity in the uterus was significantly reduced, but not in bone and cardiovascular system. Preclinical and clinical data show that ospemifene is well tolerated with no major side effects. Benefits that ospemifene may have over other SERMs is its neutral effect on hot flushes and ER-agonist effect on the vagina, improving the symptoms of vaginal dryness.<ref>{{cite journal | vauthors = Gennari L, Merlotti D, Valleggi F, Nuti R | title = Ospemifene use in postmenopausal women | journal = Expert Opinion on Investigational Drugs | volume = 18 | issue = 6 | pages = 839–49 | date = Jun 2009 | pmid = 19466874 | doi = 10.1517/13543780902953715 | s2cid = 21537130 }}</ref>