Effects of CP-336,156, a new, nonsteroidal estrogen agonist/antagonist, on bone, serum cholesterol, uterus and body composition in rat models.
We have discovered a new, nonsteroidal, potent estrogen agonist/antagonist, CP-336,156. CP-336,156 binds selectively and with high affinity to the human estrogen receptor-alpha with a half-inhibition concentration of 1.5 nM, which is similar to that seen with estradiol (4.8 nM). When given orally to immature (3-week-old) female Sprague-Dawley rats for 3 days at doses of 0.1, 1.0, 10, or 100 microg/kg x day, unlike 17alpha-ethynyl estradiol, CP-336,156 had no effect on uterine wet or dry weight. Similarly, no uterine hypertrophy was observed in aged (17-month-old) female rats treated (p.o.) with CP-336,156 at 10 or 100 microg/kg x day for 28 days. We also found that CP-336,156 decreased total serum cholesterol and fat body mass and had no effect on lean body mass in these aged female rats. In 5-month-old ovariectomized (OVX) Sprague-Dawley female rats, CP-336,156 completely prevented OVX-induced increases in body weight gain, total serum cholesterol, and serum osteocalcin at doses between 10 and 1000 microg/kg x day after 4 weeks. At these doses, CP-336,156 completely prevented OVX-induced bone loss and inhibited the increased bone turnover associated with estrogen deficiency in lumbar vertebrae, proximal tibiae, and distal femora. Similar to estrogen, CP-336,156 induced apoptosis and p53 expression with a concomitant decrease in the number of tartrate-resistant acid phosphatase-positive multinuclear cells in rat bone marrow cell cultures in vitro, suggesting that the induction of apoptosis may be a mechanism for the estrogenic activities of CP-336,156 in bone. In summary, CP-336,156 is a new, orally active, nonsteroidal, potent estrogen agonist/antagonist that has similar effects in bone as estradiol but without the uterine-stimulating effects associated with estradiol in rats.
Ke
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HZ
Department of Cardiovascular and Metabolic Diseases, Pfizer Inc., Groton, Connecticut 06340, USA. huazhu_ke@groton.pfizer.com
Paralkar
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Grasser
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Crawford
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Qi
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Simmons
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Pirie
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Chidsey-Frink
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Owen
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Smock
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Chen
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Jee
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Cameron
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Rosati
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Brown
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Dasilva-Jardine
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Thompson
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D000273:Adipose Tissue; D000375:Aging; D000818:Animals; D017209:Apoptosis; D001823:Body Composition / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects*; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D016158:Genes, p53; D009929:Organ Size / Q000187:drug effects; D015675:Osteocalcin / Q000097:blood; D010052:Ovariectomy; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects*; D015430:Weight Gain / Q000187:drug effects
D004965:Estrogen Antagonists; D011759:Pyrrolidines; D011960:Receptors, Estrogen; D013764:Tetrahydronaphthalenes; D015675:Osteocalcin; C111332:Lasofoxifene; D002784:Cholesterol