Ke H Z, Paralkar V M, Grasser W A, Crawford D T, Qi H, Simmons H A, Pirie C M, Chidsey-Frink K L, Owen T A, Smock S L, Chen H K, Jee W S, Cameron K O, Rosati R L, Brown T A, Dasilva-Jardine P, Thompson D D
Department of Cardiovascular and Metabolic Diseases, Pfizer Inc., Groton, Connecticut 06340, USA.
Endocrinology. 1998 Apr;139(4):2068-76. doi: 10.1210/endo.139.4.5902.
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.
我们发现了一种新型非甾体强效雌激素激动剂/拮抗剂CP - 336,156。CP - 336,156以1.5 nM的半抑制浓度选择性且高亲和力地与人雌激素受体α结合，这与雌二醇（4.8 nM）的情况相似。当以0.1、1.0、10或100微克/千克×天的剂量对未成熟（3周龄）雌性斯普拉格 - 道利大鼠口服给药3天时，与17α - 乙炔基雌二醇不同，CP - 336,156对子宫湿重或干重没有影响。同样，在以10或100微克/千克×天的剂量对老龄（17月龄）雌性大鼠口服CP - 336,156 28天后，未观察到子宫肥大。我们还发现，在这些老龄雌性大鼠中，CP - 336,156降低了总血清胆固醇和脂肪体量，对瘦体重没有影响。在5月龄去卵巢（OVX）的斯普拉格 - 道利雌性大鼠中，4周后，CP - 336,156在10至1000微克/千克×天的剂量下完全阻止了OVX诱导的体重增加、总血清胆固醇和血清骨钙素的升高。在这些剂量下，CP - 336,156完全阻止了OVX诱导的骨质流失，并抑制了与雌激素缺乏相关的腰椎、胫骨近端和股骨远端骨转换增加。与雌激素相似，CP - 336,156在体外大鼠骨髓细胞培养物中诱导细胞凋亡和p53表达，同时抗酒石酸酸性磷酸酶阳性多核细胞数量减少，这表明细胞凋亡的诱导可能是CP - 336,156在骨中发挥雌激素活性的一种机制。总之，CP - 336,156是一种新型口服活性非甾体强效雌激素激动剂/拮抗剂，在骨中的作用与雌二醇相似，但在大鼠中没有与雌二醇相关的子宫刺激作用。
