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/antago nist, CP-336,156. CP-336,156 binds selectively and with high affinity to the human estrogen receptor-alpha with a half-inhibition concentrat ion of 1.5 nM, which is similar to that seen with estradiol (4.8 nar). 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 mu g/kg.day, unlike 17 al pha-ethynyl estradiol, CP-336,156 had no effect on uterine wet or dry weight. Similarly, no uterine hypertrophy was observed in aged (17-mon th-old) female rats treated (po) with CP-336,156 at; 10 or 100 mu g/kg .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 t hese aged female rats. In 5-month-old ovariectomized (OVX) Sprague-Daw ley female rats, CP-336,156 completely prevented OVX-induced increases in body weight gain, total serum cholesterol, and serum osteocalcin a t doses between 10 and 1000 mu g/kg.day after 4 weeks. At these doses, CP-336,156 completely prevented OVX-induced bone loss and inhibited t he increased bone turnover associated with estrogen deficiency in lumb ar vertebrae, proximal tibiae, and distal femora. Similar to estrogen, CP-336,156 induced apoptosis and p53 expression with a concomitant de crease in the number of tartrate-resistant acid phosphatase-positive m ultinuclear cells in rat bone marrow cell cultures in vitro, suggestin g that the induction of apoptosis may be a mechanism for the estrogeni c activities of CP-336,156 in bone. In summary, CP-336,156 is a new, o rally active, nonsteroidal, potent estrogen agonist/antagonist that ha s similar effects in bone as estradiol but without the uterine-stimula ting effects associated with estradiol in rats.