Tissue distribution and pharmacological potential of SM-16896, a novel oestrogen-bisphosphonate hybrid compound

Postmenopausal osteoporosis is caused mainly by a deficiency of oestrogen w ith rapid bone loss. To target oestrogen to the bone effectively, we have s ynthesized and evaluated the effects of a novel hybrid compound of oestroge n and bisphosphonate, SM-16896. The tissue distribution pattern and pharmac ological potential are reported. Although the affinity for calf uterine oestrogen receptor was very low (IC5 0: 73.3 mu M; 1/25 000 of that of 17 beta-oestradiol (2.84 nM)), SM-16896 s howed oestrogenic activity. SM-16896 (1 mu M) induced a 4.5-fold transcript ional activity in rat osteosarcoma UMR-106 cells compared with vehicle-trea ted control, when we used the: expression vector for human oestrogen recept or and a CAT reporter plasmid containing an oestrogen-responsive element. T he distribution of SM-16896 after a subcutaneous administration to 7-week-o ld female rats was examined by radioluminography using H-3-labelled SM-1689 6. At 30 min after the administration, significant radioactivity was detect ed in the bone. At 24 h after administration, a high level of radioactivity was detected in the bone, but in the uterus it was only at a background le vel. Daily subcutaneous administration of 0.5 mg kg(-1) SM-16896 for 12 wee ks (five times per week) to 13-week-old ovariectomized rats suppressed the ovariectomized-induced reduction in bone mineral density. A bone mineral de nsity ratio of 120% was maintained compared with sham-operated rats, wherea s a relatively low suppression of uterine weight was observed (about 50% lo ss compared with sham-operated rats). In the same experiment, the implantat ion of a 17 beta-oestradiol time-release pellet (0.25 mg/pellet/90 days) al most completely suppressed the reduction of both the bone mineral density a nd uterine tissue weight. It is likely that the effect of SM-16896 on bone was due to its oestrogenic activity, since 1.0 mg kg(-1) SM-18108, the bisp hosphonate moiety of this compound, had no effect on bone in 7-week-old ova riectomized rats. The results suggest that SM-16896, a bisphosphonate-conjugated oestrogen, s howed a preference profile in the uterus and bone due to its characteristic distribution pattern compared with the natural oestrogen analogue 17 beta- oestradiol. Thus, bisphosphonate-conjugated oestrogens have the potential t o improve patient compliance in oestrogen therapy by minimizing adverse eff ects and reducing the frequency of medication.