page_title: Selective estrogen receptor modulator
section_title: Third-generation
hierarchical_section_title: Selective estrogen receptor modulator / Structure and function / Structure–activity relationships / Third-generation
caption_attribution_description: English: Skeletal structure of lasofoxifene Polski: Wzór strukturalny lazofoksyfenu
context_page_description: Selective estrogen receptor modulators are a class of drugs that act on the estrogen receptor. A characteristic that distinguishes these substances from pure ER agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.
context_section_description: Third-generation compounds display either no uterine stimulation, improved potency, no significant increases in hot flushes or even a combination of these positive attributes.
  Modifications of the first dihydronapthalene SERM, nafoxidine (see figure 10) that was a clinical candidate for the treatment of breast cancer but had side effects including severe phototoxicity, resulted in lasofoxifene ((5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol; see figure 11). 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.
  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. 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. The interactions between the ER and lasofoxifene are consistent with the general features of SERM-ER recognition. Lasofoxifenes 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.
  The 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 (1H-indo-5-ol,1-[[4-[2(hexahydro-1H-azepin-1-yl)ethoxy]methyl]2-(-4-hydroxyphenlyl)-3-methyl; see figure 10] acetic acid) 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. It is well tolerated and displays no increase in hot flush incidences, uterine hypertrophy or breast tenderness.
  Ospemifene (Z-2-(4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy)ethanol; see figure 13) 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 shoved 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.
caption: Figure 11: Chemical structure of lasofoxifene shows cis-oriented phenyls.
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