LY353381.HCL - A NOVEL RALOXIFENE ANALOG WITH IMPROVED SERM POTENCY AND EFFICACY IN-VIVO

Body weight, uteri, serum cholesterol and bones were shown previously in vivo to be sensitive to circulating levels of estrogen, as well as to synthetic, nonsteroidal ligands termed selective estrogen receptor modulators(SERM). In this study, we examined the in vivo effects of a new potent SERM on these tissues in 6-month-old, ovariectomized rats t hat were orally dosed with 0.0001-10 mg/kg/day LY353381.HCl for 5 week s. LY353381.HCl prevented the ovariectomy-induced increase in body wei ght and serum cholesterol levels of treated rats and lowered them to b elow sham levels in a dose dependent manner, with maximum efficacy sim ilar to estrogen or raloxifene. However, LY353381.HCl was consistently more potent than raloxifene, with a half maximal efficacious dose of 0.001 mg/kg for the reduction of body weight and cholesterol. In the u terus, LY353381.HCl had marginal effects on uterine weight compared to ovariectomized controls (OVX) like raloxifene, but unlike estrogen. H istological examination of uterine epithelial cell height showed littl e to no stimulatory effect of LY353381.HCl on the endometrium. Quantit ative computed tomographic analyses (pQCT) of tibiae showed that LY353 381.HCl prevented loss of bone due to ovariectomy with an ED50 of abou t 0.01 mg/kg with maximal efficacy observed at 0.1-1 mg/kg/day. Maxima lly attainable bone mineral density and content with LY353381.HCl were not significantly different from Sham or ovariectomized rats treated with estrogen or raloxifene. Interestingly, assessment of bone quality by biomechanical analyses showed that LY353381.HCl preserved the stre ngth of the femora neck and midshaft, while improving the Young's modu lus of cortical bone to beyond estrogen, raloxifene or sham levels. In uteri of immature rats treated with estrogen, LY353381.HCl antagonize d the estrogen-induced elevation in uterine weight down to vehicle-dos ed control levels with ED50 of 0.03 mg/kg/day. Therefore, LY353381.HCl was 30-100 times more potent than raloxifene in preventing ovariectom y effects on body weight, serum cholesterol and bone, while maintainin g estrogen antagonist effects on the uterus. These animal data suggest that LY353381.HCl may have advantages over estrogen or raloxifene in the prevention of bone loss and treatment of other, tissues in postmen opausal women.