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首页> 外文期刊>Journal of Medicinal Chemistry >Novel and selective calcitonin-inducing agents.
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Novel and selective calcitonin-inducing agents.

机译：新型和选择性降钙素诱导剂。

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A series of xanthine sulfonamides is presented as a class of calcitonin (CT) inducers - a potentially new method for treating diseases associated with postmenopausal bone loss such as osteoporosis. We have found that certain di-n-butylxanthine sulfonamides 4 upregulate CT transcription in a CT-luciferase reporter gene assay (CT-luci) and increase the production and release of CT in a CT secretion/RIA assay (CTS). In addition, these compounds do not have potent PDE4 inhibitory activity as do the related xanthine methylene ketones such as denbufyllene (2). One compound in particular (9) shows a transcription activation ratio (TAR) of 2.1 in CT-luci, a CTS increase of 3.6-fold, and a PDE4 (phosphodiesterase type IV) IC(50) = 4.1 microM. In addition, this compound showed a statistically significant 47% trabecular bone protection in ovariectomized-induced osteopenia (OVX) rats as determined by assay when administered for 4 weeks at 30 mg/kg/day, i. p. by quantitative computed tomography (QCT). When administered p.o., compound 9 shows 50% trabecular bone protection when administered for 3 weeks at 50 mg/kg/day, i.p. This compared with salmon CT which shows 62% trabecular bone protection when administered at 50 IU/kg/day for 4 weeks.
机译：一系列黄嘌呤磺酰胺是降钙素（CT）诱导剂的一种-一种可能的新方法，用于治疗与绝经后骨质流失相关的疾病，例如骨质疏松症。我们发现某些二正丁基黄嘌呤磺酰胺4在CT荧光素酶报告基因测定（CT-luci）中上调CT转录，并在CT分泌/ RIA测定（CTS）中增加CT的产生和释放。此外，这些化合物不具有有效的PDE4抑制活性，而与相关的黄嘌呤亚甲基酮（例如丹布菲林）一样（2）。特别是一种化合物（9）在CT-luci中显示2.1的转录激活比率（TAR），CTS增加3.6倍，PDE4（IV型磷酸二酯酶）IC（50）= 4.1 microM。另外，该化合物在以30mg / kg /天，即4周施用时经测定确定在卵巢切除诱发的骨质减少（OVX）大鼠中具有统计上显着的47％的小梁骨保护。 p。通过定量计算机断层扫描（QCT）。当口服给药时，化合物9以50mg / kg /天，腹膜内给药3周时显示出50％的小梁骨保护。相比之下，鲑鱼CT以50 IU / kg / day的剂量给药4周显示出62％的小梁骨保护性。

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