Bazedoxifene Acetate: A Selective Estrogen Receptor Modulator with Improved Selectivity

We assessed the preclinical characteristics of a novel, stringently screened selective estrogen receptor modulator, bazedoxifene acetate, including its ability to bind to and activate estrogen receptors and promote increased bone mineral density and bone strength in rats, and the effects impacting t...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 2005-09, Vol.146 (9), p.3999-4008
Main Authors: Komm, Barry S, Kharode, Yogendra P, Bodine, Peter V. N, Harris, Heather A, Miller, Chris P, Lyttle, C. Richard
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Body Temperature Regulation - drug effects
Bone and Bones - drug effects
Bone and Bones - physiology
Bone Density - drug effects
Breast Neoplasms
Carcinoma, Hepatocellular
Cell Division - drug effects
Cell Line, Tumor
CHO Cells
Compressive Strength
Cricetinae
Endometrium - drug effects
Estrogen Receptor alpha - metabolism
Estrogen Receptor beta - metabolism
Estrogens - chemistry
Estrogens - metabolism
Estrogens - pharmacology
Female
Fundamental and applied biological sciences. Psychology
Humans
Indoles - chemistry
Indoles - metabolism
Indoles - pharmacology
Ligands
Lipids - blood
Liver Neoplasms
Neurons - cytology
Osteoblasts - cytology
Rats
Rats, Sprague-Dawley
Vertebrates: endocrinology
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Summary:We assessed the preclinical characteristics of a novel, stringently screened selective estrogen receptor modulator, bazedoxifene acetate, including its ability to bind to and activate estrogen receptors and promote increased bone mineral density and bone strength in rats, and the effects impacting the uterine endometrium, breast cancer cell proliferation, and central nervous system-associated vasomotor responses in an animal model. Bazedoxifene bound to estrogen receptor-α with an IC50 of 26 nm, an affinity similar to that of raloxifene. Bazedoxifene did not stimulate proliferation of MCF-7 cells but did inhibit 17β-estradiol-induced proliferation with an IC50 of 0.19 nm. In an immature rat uterine model, bazedoxifene (0.5 and 5.0 mg/kg) was associated with less increase in uterine wet weight than either ethinyl estradiol (10 μg/kg) or raloxifene (0.5 and 5.0 mg/kg). Histological analysis revealed that coadministration of bazedoxifene also appeared to reduce raloxifene-stimulated endometrial luminal epithelial cell and myometrial cell hypertrophy. In ovariectomized rats, bazedoxifene was associated with significant increases in bone mineral density at 6 wk, compared with control, and better compressive strength of bone samples from the L4 vertebrae, compared with samples from ovariectomized animals. In the morphine-addicted rat model of vasomotor activity, bone-sparing doses of bazedoxifene alone were not associated with 17β-estradiol inhibition of increased vasomotor activity. Bazedoxifene acetate represents a promising new treatment for osteoporosis, with a potential for less uterine and vasomotor effects than selective estrogen receptor modulators currently used in clinical practice. Controlled clinical trial data will be needed to confirm these effects.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2005-0030