title: Tissue distribution and pharmacological potential of SM-16896, a novel oestrogen-bisphosphonate hybrid compound.
abstract: Postmenopausal osteoporosis is caused mainly by a deficiency of oestrogen with rapid bone loss. To target oestrogen to the bone effectively, we have synthesized and evaluated the effects of a novel hybrid compound of oestrogen and bisphosphonate, SM-16896. The tissue distribution pattern and pharmacological potential are reported. Although the affinity for calf uterine oestrogen receptor was very low (IC50: 73.3 microM; 1/25000 of that of 17beta-oestradiol (2.84 nM)), SM-16896 showed oestrogenic activity. SM-16896 (1 microM) induced a 4.5-fold transcriptional activity in rat osteosarcoma UMR-106 cells compared with vehicle-treated control, when we used the expression vector for human oestrogen receptor and a CAT reporter plasmid containing an oestrogen-responsive element. The distribution of SM-16896 after a subcutaneous administration to 7-week-old female rats was examined by radioluminography using 3H-labelled SM-16896. At 30 min after the administration, significant radioactivity was detected 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 level. Daily subcutaneous administration of 0.5 mgkg(-1) SM-16896 for 12 weeks (five times per week) to 13-week-old ovariectomized rats suppressed the ovariectomized-induced reduction in bone mineral density. A bone mineral density ratio of 120% was maintained compared with sham-operated rats, whereas a relatively low suppression of uterine weight was observed (about 50% loss compared with sham-operated rats). In the same experiment, the implantation of a 17beta-oestradiol time-release pellet (0.25 mg/pellet/90 days) almost completely suppressed the reduction of both the bone mineral density and uterine tissue weight. It is likely that the effect of SM-16896 on bone was due to its oestrogenic activity, since 1.0 mgkg(-1) SM-18108, the bisphosphonate moiety of this compound, had no effect on bone in 7-week-old ovariectomized rats. The results suggest that SM-16896, a bisphosphonate-conjugated oestrogen, showed a preference profile in the uterus and bone due to its characteristic distribution pattern compared with the natural oestrogen analogue 17beta-oestradiol. Thus, bisphosphonate-conjugated oestrogens have the potential to improve patient compliance in oestrogen therapy by minimizing adverse effects and reducing the frequency of medication.
authors.affiliation: Sumitomo Pharmaceuticals Research Center, Sumitomo Chemical Co. Ltd, Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Tsushima
authors.forename: M
authors.initials: M
authors.lastname: Yabuki
authors.forename: H
authors.initials: H
authors.lastname: Harada
authors.forename: T
authors.initials: T
authors.lastname: Katsumata
authors.forename: H
authors.initials: H
authors.lastname: Kanamaru
authors.forename: I
authors.initials: I
authors.lastname: Nakatsuka
authors.forename: M
authors.initials: M
authors.lastname: Yamamoto
authors.forename: M
authors.initials: M
authors.lastname: Nakatsuka
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D004164:Diphosphonates / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism*; D015394:Molecular Structure; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism*; D014018:Tissue Distribution; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
chemical_list: D004164:Diphosphonates; D011960:Receptors, Estrogen; C406720:SM 16896